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Menopause Matters

Exogenous Hormones and Migraine Risk Management in Perimenopausal Patients

David Harari, MD; Lee P. Shulman, MD

ncreased risk of migraine headaches in reproductive-aged women correlates with estrogen withdrawal. In those with regular menstrual cycles, up to 60% of migraine headaches occur during the late luteal phase or during menstruation.¹ In perimenopausal women, migraine associated with estrogen deficiency may occur at less predictable intervals as a consequence of declining ovarian function and fluctuating levels of serum estrogen. Perimenopausal women with migraine are particularly strong candidates for maintenance estrogen therapy because of additional potential benefits with regard to reducing hot flashes, mood instability, and other perimenopausal symptoms.²

The association between migraine and estrogen withdrawal during the menstrual cycle is sufficiently well established, and several formal definitions have been proposed.^3,4 During the perimenopausal period, which begins 2 to 7 years before menopause, serum estradiol levels become highly variable.⁵ This variability, corresponding with increasing menstrual irregularity, may produce a variety of symptoms (eg, hot flashes and sleep disturbances) in estrogen-sensitive tissues. It may also be associated with adverse but asymptomatic changes on physiologic processes such as bone metabolism.^6,7 In preventing migraine due to estrogen deficiency, the most important goal may be stabilization of estrogen levels to prevent fluctuations.

The likelihood that preventing abrupt reductions in circulating estrogen is more important than augmenting estrogen in women with hormone-related migraine is suggested by the relative freedom from migraine in postmenopausal women.⁸ As in prepubertal females, (who, unlike reproductive-aged females, have no greater risk of migraine than males of the same age⁹), postmenopausal females may enjoy a relative protection from migraine because, although low, their estrogen levels remain constant. In contrast, risk of migraine is not only increased during the estrogen-withdrawal phase of the menstrual cycle but also in other conditions associated with abrupt estrogen decline, such as the postpartum state.¹⁰

The most likely route by which a sudden decline in estrogen induces migraine is through the effect of this sex hormone on cerebrovascular function. Estrogen is a vasodilator¹¹ and may be important to homeostasis of vascular smooth muscle on which estrogen receptors have been isolated.¹² Among other activities, estrogen has been found to maintain concentrations of magnesium, an element important to vascular function in the smooth muscle cells of the cerebral vasculature.¹³ It has been speculated that an abrupt change in the level of circulating estrogen triggers vasospasm in the cerebral circulation and the nerve impulses that produce migraine.¹⁴ Other factors, such as change in neurotransmitter activity by an independent or related route, may play an important contributory role.¹⁵

STRATEGIES FOR PREVENTION OF PERIMENOPAUSAL MIGRAINE

In women with menstrual migraine, prophylaxis can be achieved with brief courses of low-dose estrogen supplementation initiated at the end of the luteal phase and maintained until the end of the menstrual period.^16,17 In dose-ranging studies, serum estradiol levels maintained between 60 to 80 pg/mL have been more effective than therapies that yield lower levels.¹⁸ This range can typically be achieved with 0.625/day of oral conjugated equine estrogens (CEE) or 0.25 to 0.1 mg/day of transdermal estradiol. However, oral CEE, unlike estradiol administered transdermally, has not been consistently effective.¹⁹ This may be related to the type of estrogen or differences in steady-state pharmacokinetics by these two methods of drug delivery at sensitive tissues.

For perimenopausal migraine, prophylaxis may require lower doses of exogenous estrogen than those employed to prevent migraine in women with regular menstrual cycles. Unlike the abrupt withdrawal of estrogen associated with involution of the corpeus luteum, the suspected etiology of migraine in perimenopausal women is relatively modest fluctuations in circulating estrogen associated with declining ovarian function. The goal in these patients, some of whom may have lower peak levels of estrogen than those of younger reproductive-aged women, is to modify estrogen variability.

Specific regimens of exogenous estrogen in the perimenopausal female should be evaluated in the context of other potential health-related benefits. Up to 85% of perimenopausal women experience hot flashes.²⁰ Other risks of estrogen deficiency due to declining ovarian function include mood lability, vaginal dryness, and sleep disturbances. Also of importance, women who enter the perimenopausal period (defined as irregular menstrual cycles) have significantly greater bone loss than asymptomatic women matched for age and baseline bone mineral density.²¹ Declining levels of estrogen may also be relevant to protection from cardiovascular disease, a progressive process that begins years before events and is the most important cause of mortality in postmenopausal women as it is in men.²²

Oral contraceptives (OCs) used in conventional fashion do not appear to be a reliable option for prevention of menstrual migraine either in perimenopausal women or those with regular menstrual periods. In a review of 23 studies, 12 of the studies associated OCs with an exacerbating effect, and eight found no effect.²³ Only three associated OCs with benefit. As OCs reproduce the decline in estrogen during the withdrawal phase of the menstrual cycle, these results are consistent with the premise that the benefit of exogenous estrogen for migraine prophylaxis is derived more from avoiding variability in hormone levels than in supplementing existing levels.

The goal of providing low but constant levels of estrogen may also be relevant to other therapeutic goals in the perimenopausal woman, including prevention of mood lability and control of sleep disturbances. Very low levels of exogenous estrogen appear to be adequate for maintaining bone metabolism.²⁴ Although such symptoms as hot flashes are dose sensitive, it is prudent to initiate hormone therapy with relatively low doses, titrating upwards for symptom control. This may be expected to reduce the risk of inducing estrogen-related symptoms, such as breast tenderness, as well as the potential to trigger migraine.

In perimenopausal women who continue to have menstrual periods, unopposed estrogen does not threaten the endometrium. For migraine prophylaxis, transdermal delivery of estrogen may have several advantages over other methods of delivery, including oral and sublingual formulations. In particular, transdermal delivery avoids the peaks and troughs of intermittent dosing, an important potential variable when the goal is steady-state hormone levels. While oral CEE has a half-life ranging from 10 to 15 hours, permitting once daily dosing,²⁵ transdermal patches are replaced every 3.5 to 7 days. This reduces the risk of diminished circulating estrogen as a result of missed doses as well as the daily nadir in estrogen level prior to a next dose.

It has also been suggested that transdermal delivery, which avoids the adverse effects of first-pass metabolism on serum triglycerides, provides a more favorable estradiol-to-estrone ratio, a variable considered a potential risk factor for migraine.²⁶ The efficacy of transdermal estradiol against menstrual migraine has been demonstrated in numerous double-blind trials with a variety of specific formulations, including those patches replaced weekly.^27-29

Hormone therapy is one of many approaches to prophylaxis of migraine, even those presumed to be triggered by fluctuations in estrogen. In menstrual migraine, therapeutic benefit has been associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs),³⁰ ergotamines,³¹ and triptans.³² The role of magnesium dysregulation has been supported by benefit achieved with magnesium supplementation.³³ However, estrogen therapy is particularly attractive in the perimenopausal female because of adjunctive benefits. These adjunctive benefits can be measured empirically in women with symptoms of estrogen deficiency, such as hot flashes, but it is important to consider potential protection against subclinical disorders in such estrogen-sensitive tissues as bone and the central nervous system.

Exogenous estrogen has not been well studied in the treatment of migraine, and it is unclear whether orally or transdermally administered hormone would have a sufficiently rapid effect to abort a pathogenic process that is already underway. Due to the abrupt and often intense symptoms of migraine, prophylaxis appears to be a preferable approach when recurrent episodes are anticipated. However, treatments that have been effective for aborting other types of migraine, such as NSAIDs and triptans, also appear to be effective in menstrual migraine and would, therefore, be likely to be effective in perimenopausal migraine.

Migraine prophylaxis is achieved empirically. Therapies may provide a relative rather than an absolute reduction in migraine risk. Moreover, it may be necessary to judge benefits over several weeks, adjusting therapeutic strategies as necessary to improve migraine control. While estrogen therapy should be considered a first-line strategy for migraine prophylaxis in the perimenopausal female, it is reasonable to consider triggers other than estrogen deprivation and alternative treatments in management.

CONCLUSION

The controversy surrounding the findings of the Women’s Health Initiative and Heart and Estrogen/progestin Replacement Study (parts I and II) concerns a specific formulation and dose of combination hormone therapy (CEE 0.625 and medroxyprogesterone acetate 2.5 mg taken daily) used by menopausal women. Owing to the specific nature of the formulation and population studied, one should not extrapolate those findings to other sex steroid therapies used by nonmenopausal women. Further studies are obviously needed to determine the benefits and risks, if any, of low-dose sex steroid therapies in nonmenopausal women outside of the likely short-term benefits described herein.

An increased incidence of migraine in women who have entered a perimenopausal period of irregular menstrual cycles, particularly those with a history of menopausal migraine, are candidates for estrogen therapy. Relatively low doses of unopposed estrogen may be effective in stabilizing estrogen to prevent the sudden declines at estrogen-sensitive tissues, such as the cerebral vascular system, which is suspected of mediating menopausal migraine. Transdermal estrogen may be superior to oral estrogen because of its ability to ensure favorable steady-state pharmacokinetics. In women receiving low-dose estrogen therapy to prevent migraine during the perimenopausal period, there is a strong potential for an array of adjunctive health benefits, including protection against hot flashes, mood disorders, sleep disturbances, and unfavorable changes in bone metabolism.

David Harari, MD, is an OB/GYN in private practice in San Diego, Calif. Lee P. Shulman, MD, is chairman, Department of Obstetrics and Gynecology, University of Illinois at Chicago.

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