Headaches In Women

Laura Guzdziol Reilly, M.D.
Laura Guzdziol Reilly, M.D. is a Neurologist at Naval Air Station, Jacksonville.

Introduction

While the affliction of headache in men and women has been described as early as 3000 BC, epidemiologic details and gender differences in headache frequency have only recently been elucidated. A recent population-based study estimated that 90% of men and 95% of women experience unprovoked headaches annually.1 Triggering events that provoke migraines specifically, such as missed meals, too much or too little sleep, flashing lights, and strong odors affect men and women similarly. However, in many women, the changing hormonal environment is an additional trigger. Further support of the impact of the hormonal milieu in females is hinted at in Bille's 1962 classic study of 9059 children.2 He noted that there was no difference between the sexes in the incidence of migraine before puberty. In the 7 to 9 year old range, the prevalence of migraine was approximately 2.5% in both girls and boys. However, after the age of 11 years, there was an increasing female predominance, which became more marked in the 13 to 15 year old age group. The median age of menarche in developed countries is 12.8 years (range - 9.1 to 17.7) corresponding to Bille's findings.3 Migraine without aura is the headache that rises most frequently at the onset of menarche among females.

Other investigators have studied the prevalence of migraine over the female life cycle. It is estimated that the female to male ratio of migraine is approximately 3:1. This gender difference increased steadily from menarche, peaked at 42 years old, and declined thereafter.4 The climacteric — the time when ovarian function begins to wane — begins at approximately 40 years old. This stage can last up to 20 years in some women with menopause finally occurring at approximately 50.8 years on average.3 Menopause has a variable effect on migraine frequency, and surgical menopause via bilateral oophorectomy generally results in a less favorable course when compared with physiologic menopause. The consensus is that there is no role for surgical sterilization as a treatment for menstrual migraine headaches.

What is a menstrual migraine? Even the Headache Classification Committee of the International Headache Society has not come to agreement on the definition for menstrual migraine (See Tables 1, 3 and 4 for the IHS Classification of Headaches — Overview, Migraines, and Tension Type, respectively). The committee does state the following: "Migraine without aura may occur almost exclusively at a particular time of the menstrual cycle i.e. the so-called menstrual migraine. Generally accepted criteria for this entity are not available. It seems reasonable to demand that 90% of attacks should occur between two days before menses and the last day of menses, but further epidemiological knowledge is needed."5 A recent pilot study undertaken with strict attention to keeping an accurate headache log showed that only 7% of the women in the study conformed to the definition of menstrual migraine defined to be "migraines without aura that occur regularly on day one of menstruation +/- 2 days and at no other time."6

Mechanisms

Given the difficulty in defining menstrual migraine and the inconsistency of definitions in the literature, determination of the impact of hormonal fluctuations of the steroid hormones estrogen and progesterone are limited. One study comparing levels of these hormones in women with and without migraines yielded no significant differences.7 This study, however, cannot exclude an individual sensitivity to the normal, cyclic endocrine changes of the ovarian cycle as a trigger for a migraine attack.

Somerville conducted some interesting work on the roles of estrogen and progesterone in triggering a migraine. He found, in a small group of six migraineurs with exclusively menstrual attacks, that injections of progesterone in oil given daily three to six days prior to the expected date of menstruation merely postponed menstruation in four of the six subjects. Five of the six experienced their typical migraines. Additionally, none of the women developed migraines in association with falling progesterone levels.8

He addressed estrogen withdrawal as well in a total of 14 women with exclusively menstrual migraines. He showed that migraines could be postponed by maintaining high plasma estradiol levels via an intramuscular injection of the long-acting estradiol valerate in oil. As the endogenous progesterone levels fell, the expected menstrual bleeding occurred without headache. It was only when the plasma estradiol levels began to fall that the subjects experienced a typical migraine attack. The administration of short-acting estrogen did not produce the same result. These findings led Somerville to postulate that prolonged estrogen exposure, such as that occurring during the luteal phase but not at ovulation, is necessary to trigger an estrogen withdrawal migraine.9, 10 Whether estrogen withdrawal is the primary mechanism for menstrual migraine or simply primes the blood vessels to be more susceptible to other factors implicated in migraine is not yet known.11 It is known that estrogens and noradrenaline, serotonin, dopamine and endorphins have close interrelationships, but further research with a standard definition for menstrual migraine will need to be conducted to fully evaluate the role, if any, of these neurotransmitters in the generation of migraine.

Finally, the role of prostaglandins in the generation of menstrual migraines must be reviewed. It is well known that the introduction of prostaglandins into the systemic circulation of normal subjects with no history of migraine can cause throbbing headache, nausea, vomiting and even visual aura.12 It is also known that there is a threefold rise in prostaglandin levels in the uterine endometrium from the follicular to the luteal phase with a further increase during menstruation.3 The maximum levels of prostaglandins and their metabolites are measured in the systemic circulation during the first 48 hours of menstruation. Some researchers have pointed to prostaglandin release as a possible mechanism for menstrual migraine.13 To support this theory is the observation that prostaglandin inhibitors effectively prevent migraine attacks in some women.13, 14  In summary, biologic control of the menstrual cycle is extremely complex and there is likely more than one mechanism or an interrelationship of mechanisms responsible for the generation of the menstrual migraine.

Management

Sixty percent of women have attacks of migraine associated with menses, and 7-13% have their attacks exclusively with menses. The initial treatment should be the same as that for non-menstrual migraine.16 General measures for all migraineurs should include reassurance, analysis and elimination of triggers via the review of a faithfully kept headache log, use of abortive and prophylactic therapies, psychological modalities such as relaxation techniques and biofeedback, and good sleep hygiene (Table 2).

Table 2. Sleep Hygiene

  • Maintain a regular sleep-wake cycle. Get out of bed early in the morning whether or not you have slept well.
  • Preserve your bed as a haven for sleep and sex. Avoid other waking activities in bed (such as reading or watching television in the evening).
  • Minimize alcohol consumption and avoid caffeine during the afternoon and evening. Don't eat heavily shortly before bed.
  • Make sure your bedroom environment is conducive to sleep. It should be cool, quiet, and dark.
  • If your mind is preoccupied by something such that you can't fall asleep, put the problem to rest by writing it down in a sentence or two and set it aside until morning.
  • Don't try too hard to fall asleep; it will only make things worse. If you can't fall asleep after 20 to 30 minutes, get out of bed, do something relaxing, and go back to bed when you feel sleepy.

Since perimenstrually related migraines typically occur in association with other symptoms (breast tenderness and swelling, nausea, mood changes), increasing the dose of prophylactic medication perimenstrually or the use of intermittent prophylaxis may control these premenstrual associated, resistant migraines. For women with exclusive menstrual migraines, effective treatment can consist of the perimenstrual use of a combination of preventive or symptomatic medications.

The first line pharmacologic agents should seek to inhibit prostaglandin production, which may be enhanced in menstrual migraineurs. NSAIDs are effective if given in adequate doses 1 to 2 days prior to the expected onset of headache and continued for the duration of the vulnerability. One needs at least a three-month log of the headache pattern to establish this vulnerable time-frame. This author generally begins with naproxen sodium given BID, an especially effective agent if dysmenorrhea is a coincident complaint. If the propionic acid class is ineffective, agents from other classes are tried.

Ergotamines can be used preventively at the time of menstrually associated migraines without significant risk of developing ergot dependence, assuming that the agent is not used frequently during other times of the month as well. Ergotamine tartrate, at bedtime or twice a day, is also, an effective prophylactic agent.17 Ergotamine in combination with belladonna and phenobarbital (Bellergal®) may be useful in treating both headache and premenstrual symptoms (PMS).18 DHE, now available in a nasal spray, is effective in preventing and/or terminating menstrual migraines.19 Sub-cutaneous sumatriptan has been studied prospectively and found to be useful in the relief of menstrual migraines. However, many of the subjects did not have exclusively menstrual migraines. The newer triptans should also be considered, if sumatriptan fails.

For the severe menstrual migraine not controlled by NSAIDs, ergots or the triptans, analgesics combined with narcotics may be used. If this is ineffective, one may choose a three to five day burst of corticosteroids, the use of IV DHE, or the use of major tranquilizers (chlorpromazine, haloperidol). However, in the later case, the risk of developing tardive dyskinesia (TD) must be weighed against the benefits; it generally does not develop unless the agent is utilized for 6 or more months, but there are cases of TD developing with far less exposure to neuroleptics. This potential side effect should be openly discussed with the patient prior to initiating therapy. Chlorpromazine administered IV has been established as an efficacious abortive treatment, however. One must also carefully monitor the patient's blood pressure after such treatment.

Hormonal management can be considered if the forgoing treatments have proven ineffective. For those few patients with intractable menstrual migraines, especially when associated with severe dysmenorrhea, combinations of estrogens and progestogens in the form of oral contraceptives may be a useful approach in an attempt to stabilize estrogen levels during the luteal phase of the cycle. Practitioners have also used the approach of maintaining low estrogen levels via medically (never surgically) induced menopause. Danazol, an androgen derivative, has been utilized as a prophylactic agent around the time of menses. Tamoxifen, an anti-estrogen, has also been used on days 7 to 14 of the luteal phase. Dopamine agonists, such as bromocriptine, are used with good effect during the luteal phase of the menstrual cycle and can greatly decrease some of the premenstrual symptoms such as breast swelling, irritability and headache.

Management Of Peri- And Post-Menopausal Migraines

For the woman entering the climacteric, symptoms of hot flushes, vasomotor changes, sleep difficulties and irritability may be managed with oral estrogen replacement therapy alone or in combination with cyclic progestins, depending on whether the uterus is present. While hormonal replacement therapy (HRT) is beneficial in treating perimenopausal symptoms as well as preventing osteoporosis, some women may experience an increase in migraine as a result. One should consider switching the estrogen to a percutaneous gel form as it has been shown to produce higher, more stable levels in the serum. The trans-dermal estrogen patch may also be tried, however, the serum levels are not as stable as with the gel. Orally administered estrogens are known to have erratic absorption and, as a result, produce widely variable fluctuations in serum estrogen levels. Consideration of reducing the dose of estrogen or changing the type of estrogen from a conjugated form to a pure estrone may also significantly reduce the headache frequency and/or severity. Should the migraines increase in the week off of estrogen replacement therapy, the use of continuous estrogens should be considered. Migraineurs who do not wish to have HRT during perimenopause, may get relief from severe hot flashes with clonidine prophylaxis. Again, there is no evidence that hysterectomy or oophorectomy is an effective or reasonable treatment for migraines at any age.

Adverse Effects Of Oral Contraceptive Use In The Migraineur

Headache is a common side effect of oral contraceptive use. The onset of migraine is ten times more common in women starting the combined oral contraceptive pill (OCP) compared with controls.20 If migraines are related to the pill free-week, the ratio of estrogen to progestogen should be altered. One can also consider tricycling the pill i.e. taking three packets without a break, or using estrogen supplements during the pill-free week.

Migraine, Oral Contraceptive Use And Stroke Risk

Synthetic estrogens cause prothrombotic changes in the blood that may be sufficient to result in a thrombotic stroke. The combined OCP is contraindicated in migraine with aura. OCPs should be immediately stopped should focal neurologic symptoms develop. An alternative method of birth control is then instituted.

Some of the most recent research has indicated a significant association between migraine and stroke in women aged 45 or less. In a case-controlled study, there was an approximately four-fold increased risk of stroke in women who smoked.21 The risk of stroke was 3x control for migraine without aura and 6x the risk of controls for migraine with aura. Young women who choose to smoke increased their stroke risk to approximately 10x control, more than 3x greater then young women without migraine who smoke. For young women with migraine on OCPs, the risk of stroke is 14x control, and 4x the risk for women on OCPs who do not suffer from migraine. There is a dose-effect relationship between risk of stroke and the dose of estrogen; the risk increasing with the higher dose pills. The absolute risk of stroke in the patient population translates to about 19/100,000 per year, which is a low rate overall.22

For postmenopausal estrogen therapy with and without progestins, there is no convincing evidence to date that there exists a beneficial or adverse influence on stroke risk. It may be safely used for its cardioprotective and beneficial influence in reducing osteoporosis as well as symptomatic treatment.

Migraines And Pregnancy

Lance23 aptly summarizes the situation: "The only hormonal treatment which is at least 60% effective is pregnancy." Several studies have shown that approximately 70% of migraineurs improve during pregnancy. However, each pregnancy is different and because migraines improved in one does not suggest that they will improve in the next, they may even worsen. Ten percent of women develop their first migraine during pregnancy. Treatment of such headaches encompasses a broad number of issues including adverse effects of diagnostic testing and drug effects on the fetus and will not be discussed further.

Summary

Every woman is influenced by her ever-changing hormonal milieu throughout the life cycle. Some have unpleasant cyclical syndromes, others no appreciable adverse effects. Certainly there remains much work to be done to better understand the complex interactions between hormones, neurotransmitters, prostaglandins and, likely, other contributing factors, the sum total of which is recognized as the menstrual cycle. As well, an agreed upon definition of menstrual migraine will help further our understanding of the specific mechanisms responsible for this phenomenon. Even though uncertainties abound regarding the specific pathophysiology of the menstrual migraine, PMS, heacache associated with OCP use and in the climacteric, astute observation has yielded a general approach to headache treatment in managing such patients.

REFERENCES

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  2. Bille B. Migraine in school children. Acta Paediatrica Scandinavica. 1962; 51(suppl 136): 1-151.
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Jacksonville Medicine / April, 2000

 

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