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Hormonal Management of Migraine Associated With Menses and the Menopause: A Clinical Review

CME

  • Elizabeth Loder, MD;
  • Paul Rizzoli, MD;
  • Joan Golub, MD

From the Departments of Neurology (Division of Headache and Pain) (Drs. Loder and Rizzoli); and Obstetrics and Gynecology (Dr. Golub); Harvard Medical School, Boston, MA, USA; John R. Graham Headache Centre (Drs. Loder and Rizzoli) Brigham and Women’s (Drs. Loder, Rizzoli, and Golub); and Faulkner Hospitals, Boston, MA, USA (Drs. Loder and Rizzoli).

Address all correspondence to Dr. Elizabeth Loder, MD, 1153 Centre Street, Boston, MA.

Accepted for publication November 20, 2006.

Abstract

Go to sectionTop of pageAbstractDEFINING HORMONALLY ASSOCIATED…CHARACTERIZING HORMONAL HEADAC…TRANSLATING KNOWLEDGE INTO TRE…HORMONAL TREATMENT STRATEGIES …OTHER HORMONAL TREATMENTS FOR …HORMONAL INTERVENTIONS FOR MIG…HRT AND POSTMENOPAUSAL HEADACH…CONCLUSIONReferences

Objective.—This article reviews hormonal strategies used to treat headaches attributed to the menstrual cycle or to peri- or postmenopausal estrogen fluctuations. These may occur as a result of natural ovarian cycles, or in response to the withdrawal of exogenously administered estrogen.

Background.—A wide variety of evidence indicates that cyclic ovarian sex steroid production affects the clinical expression of migraine. This has led to interest in the use of hormonal treatments for migraine.

Methods.—A PubMed search of the literature was conducted using the terms "migraine," "treatment," "estrogen," "hormones," "menopause," and "menstrual migraine." Articles were selected on the basis of relevance.

Results.—The overarching goal of hormonal treatment regimens for migraine is minimization of estrogen fluctuations. For migraine associated with the menstrual cycle, supplemental estrogen may be administered in the late luteal phase of the natural menstrual cycle or during the pill-free week of traditional combination oral contraceptives. Modified contraceptive regimens may be used that extend the duration of active hormone use, minimize the duration or extent of hormone withdrawal, or both. In menopause, hormonally associated migraine is most likely to be due to estrogen-replacement regimens, and treatment generally involves manipulating these regimens. Evidence regarding the safety and efficacy of these regimens is limited.

Conclusions.—Hormonal treatment of migraine is not a first-line treatment strategy for most women with migraine. Evidence is lacking regarding its long term harms and migraine is a contraindication to the use of exogenous estrogen in all women with aura and those aged 35 or older. The harm to benefit balances of several traditional nonhormonal therapies are better established.

Cyclic ovarian sex steroid production may affect the clinical expression of migraine, as demonstrated by a wide variety of clinical, epidemiologic, and basic science observations. Clinical observations include the fact that attacks of migraine in some women correlate with the menstrual cycle and improve when hormonal cycling ceases during pregnancy or after menopause.16 Epidemiologic evidence includes the fact that migraine is more common in women than in men, with incidence peaking in the year of menarche.3 Experimental evidence has established the influence of sex steroids on nociceptive and antinociceptive pathways known to be involved in pain and migraine.711,12

Based on quasi-experimental observations in a small number of women with menstrually triggered migraine, Somerville proposed that the late luteal phase decline in estrogen levels could trigger migraine. In women who predictably experienced migraine attacks around the time of the menstrual flow, he administered supplemental estrogen. Expected attacks of migraine were postponed until the effects of the supplement wore off. In contrast, progesterone supplementation was not effective in preventing menstrual attacks.1317 Subsequently, multiple lines of evidence have confirmed the validity of estrogen withdrawal, after periods of sustained high levels, as a migraine trigger in premenopausal women.

A study by Lichten et al supports estrogen withdrawal as a migraine trigger in postmenopausal women. He administered 5 mg intramuscular depo-estradiol to 16 postmenopausal women with migraine and 12 nonmigraineurs, and monitored estrogen levels and headache activity for the next 28 days. All women had been on estrogen replacement therapy prior to study entry. No woman experienced headache during the 14 days following the injection, but as estrogen levels declined, all 16 of the migraineurs developed headache, at an average of day 18.5 ± 2.8 and a serum level of 46.4 ± 5.6 pg/mL. No woman without migraine experienced headache during estrogen withdrawal.18

The most plausible explanation for estrogen withdrawal as a trigger for migraine is the hypothesis put forward by Welch et al of a "mismatch" between the timing of estrogen effects on gene regulation in the central nervous system, and its effects on cell membranes.19 He suggests that under ordinary circumstances estrogen-mediated gene regulation "modulates inhibitory peptide function in the trigeminal nerve." This counterbalances estrogen-mediated increases in neuronal membrane excitability. When estrogen levels fall, their down-regulating effect on inflammatory genes is removed and compensatory mechanisms cannot always be invoked quickly enough to avoid the possibility of headache in women who have "the neuronal excitability that is an inherent feature of the migraine-prone brain."19

It is thus not surprising that some women with migraine are particularly vulnerable to attacks during the late luteal phase of the natural menstrual cycle, the pill-free week of combined hormonal contraceptive regimens, or the perimenopause, to name just a few events that may be characterized by periods of estrogen decline after sustained high levels. This review focuses on hormonal strategies used to treat headaches attributed to the menstrual cycle or to peri- or postmenopausal estrogen fluctuations. These may occur as a result of natural ovarian cycles, or in response to the withdrawal of exogenously administered estrogen.

DEFINING HORMONALLY ASSOCIATED MIGRAINE

 Go to sectionTop of pageAbstractDEFINING HORMONALLY ASSOCIATED…CHARACTERIZING HORMONAL HEADAC…TRANSLATING KNOWLEDGE INTO TRE…HORMONAL TREATMENT STRATEGIES …OTHER HORMONAL TREATMENTS FOR …HORMONAL INTERVENTIONS FOR MIG…HRT AND POSTMENOPAUSAL HEADACH…CONCLUSIONReferences

It is difficult to be certain whether an observed temporal association between an individual migraine headache and a particular hormonal event is causal or coincidental. This is especially true in women with frequent headaches, in whom some headaches will occur in association with hormonal events by chance alone. The authors of a population-based study of young women with at least 2 migraines a month concluded that menstruation accounts for only "a small proportion of attacks in young women with frequent migraine."20 If serum estrogen levels could be measured, it might be easier to identify a relationship between hormonal fluctuations and headache. However, direct measurement, through blood or urine tests, of the hormonal changes suspected of triggering headaches currently is impractical in clinical practice.

This practical diagnostic difficulty is the most important limitation of hormonal headache definitions in the International Classification of Headache Disorders (ICHD-II).21 Table 1 summarizes ICHD-II definitions of hormonal headaches. In general, these bring welcome standardization to a field characterized by serious diagnostic inconsistencies and variability.22 However, criteria for both menstrual migraine and estrogen withdrawal headache rely on vaginal bleeding as a surrogate marker of internal hormonal changes. They thus cannot be applied to women with a functioning hypothalamic-pituitary-ovarian axis but no uterus, or those who may have undergone procedures such as endometrial ablation, even though the mechanism of cyclically occurring headaches in these cases may be identical to that in menstruating women. In fact, the hormonal nature of such headaches cannot be satisfactorily reflected using ICHD-II, a logical inconsistency that should be remedied in future revisions.

In the case of menstrual-associated headaches, longitudinal diary information that demonstrates a consistent pattern of headaches in close temporal association to the period is necessary to corroborate the impression of a hormonal trigger and plan the timing of treatment. Candidate criteria for menstrual migraine that debuted in ICHD-II require that headaches meeting migraine criteria occur in 2 of 3 menstrual cycles during a 5-day window extending from 2 days before to 3 days after menses.21

ICHD-II distinguishes between "pure" menstrual migraine (PMM) and "menstrually-related migraine" (MRM). Its authors explain the distinction by asserting that "hormone prophylaxis is more likely to be effective for pure menstrual migraine." As no strong scientific evidence supports this statement, it seems possible that the authors may have meant that hormone prophylaxis is more feasible, practical or successfully implemented in PMM than in MRM. In PMM the hormonal trigger for every attack can be assumed and anticipated, making it easy to time and target treatment. In women with MRM, who are susceptible to nonhormonal triggers and by definition have more frequent migraine than women with PMM, it is less possible to be certain that hormonal treatment of a particular attack is required or accurately timed.

ICHD-II also recognizes a category of headache termed "Exogenous hormone-induced headache."21 In keeping with the temporal associations required to diagnose other secondary headache disorders, criteria require that the headache begin or "markedly worsen" within 3 months of beginning exogenous hormones, and "resolve or revert to its previous pattern" within 3 months of stopping exogenous hormones.

However, despite strongly held beliefs and numerous anecdotal reports suggesting that exposure to contraceptive hormones can produce headache, the scientific evidence for this is not especially strong.23,24 A major failing of many studies invoked to support such a link is that they do not distinguish between hormone exposure and hormone withdrawal; a great deal of evidence suggests it is the latter which produces headache.2528 Many such studies also do not distinguish between migraine with and without aura, even though there is reason to believe these 2 migraine subtypes may respond differently to high estrogen levels. High stable estrogen levels generally protect against headache, but may be provocative of aura.2932 Interestingly, though, there is no ICHD-II category for "exogenous hormone-induced aura."

Similar problems dog attempts to diagnose and classify headaches connected to the perimenopause or menopause. Here, too, there is uncertainty about whether it is hormonal exposure, withdrawal, or both that can trigger headaches.33 Again, studies showing a connection between headache and use of hormonal replacement therapies (HRT) shed no light on the reason for that association and many do not distinguish among sequential, cyclic or continuous methods of administering treatments.3436 As with oral contraceptives, studies that have examined these regimens separately generally support the view that it is estrogen withdrawal rather than exposure that is responsible for headache.37

Discussions of "menopausal headaches" often consider headaches that occur during the perimenopausal transition along with those that occur after menopause. In fact, a distinction between these 2 life stages is clinically important in any discussion of headaches. Postmenopausal status in previously menstruating women is generally defined as the absence, for 12 consecutive months, of menstrual bleeding.38 It is characterized by stable, low estrogen levels. In keeping with the importance of estrogen withdrawal as a headache trigger, the majority of women with hormonally influenced migraine report significant headache improvement after menopause.2,34,39,40

The perimenopause is characterized by a "change in ovarian hormones, feedback relationships, and clinical experiences beginning in women age 35-50 with regular flow and ending 1 year after the final menstrual flow."41 Clinically, it is marked by increased variability in the length of menstrual cycles and missed menstrual periods.42 Although one might expect that estrogen levels in premenopausal women decline smoothly and gradually during this transition, estradiol levels are in fact increased during the perimenopause, and often are higher than those of the premenstrual years.43 Estradiol receptors also may be increased in tissues.41 These factors probably explain the amply documented worsening of headaches during the perimenopausal transition, and the fact that the average age of women in most headache clinics and clinical trials is in the 40s.44 Estrogen declines markedly in the first year after the last menstrual period and then remain low and stable.

In contrast to premenopausal women, where exogenous hormone exposure largely consists of contraceptive regimens, both contraceptive and HRT regimens may be used in perimenopausal women. Since unintended pregnancy can still occur, some perimenopausal women will be on hormonal contraception, while others may begin to use typical hormone replacement regimens.45

CHARACTERIZING HORMONAL HEADACHES

 Go to sectionTop of pageAbstractDEFINING HORMONALLY ASSOCIATED…CHARACTERIZING HORMONAL HEADAC…TRANSLATING KNOWLEDGE INTO TRE…HORMONAL TREATMENT STRATEGIES …OTHER HORMONAL TREATMENTS FOR …HORMONAL INTERVENTIONS FOR MIG…HRT AND POSTMENOPAUSAL HEADACH…CONCLUSIONReferences

The question of whether hormonally triggered headaches are more severe or treatment-refractory than similar nonhormonally triggered headaches is important. Unusually severe or difficult to treat headaches sometimes are believed to warrant special or more hazardous treatment regimens than other headaches. Studies of treatment-seeking women in specialty headache clinics generally suggest that hormonally induced headaches are more severe than others.4,46,47 However, this is not clearly true in the general population of women with headache. In a population-based diary sample of 81 women, information from over 7000 diary days showed headache was more likely during 2 days before and the first 2 days of menstruation, but overall these headaches were not more severe than headaches at other times. Attacks that were classified as migraine were significantly more severe but the differences were small.48 It also is not clear that hormonally triggered headaches respond less well to treatment than nonhormonally triggered headaches in population-based samples of women with migraine.

TRANSLATING KNOWLEDGE INTO TREATMENT

 Go to sectionTop of pageAbstractDEFINING HORMONALLY ASSOCIATED…CHARACTERIZING HORMONAL HEADAC…TRANSLATING KNOWLEDGE INTO TRE…HORMONAL TREATMENT STRATEGIES …OTHER HORMONAL TREATMENTS FOR …HORMONAL INTERVENTIONS FOR MIG…HRT AND POSTMENOPAUSAL HEADACH…CONCLUSIONReferences

There is no evidence that hormonal treatments for migraine are more effective or safer than nonhormonal treatments. Most hormonal treatments for migraine have been tested in case series or small clinical trials in selected populations that are inadequate to fully establish their harm to benefit balance. The long-term effects of additional or increased hormone exposure from these regimens are unknown. Total exposure to hormones increases significantly with extended duration regimens, although daily hormone exposure does not increase and there is no accumulation of hormones. A recent Cochrane report on extended duration or continuous contraceptive regimens concluded that "the long term health effects have not been documented."49

No hormonal treatment regimen has United States Food and Drug Administration (FDA) approval for a migraine or headache indication. Most importantly, because of the risk of ischemic stroke, treatment guidelines from 3 authoritative groups recommend against the use of estrogen-containing contraceptives in many women with migraine.5053 Results of the Women’s Health Initiative Study have led to recommendations against the routine use of estrogen replacement therapy in most women.5456

Thus, a diagnosis of hormonally associated migraine adds hormonal therapy to the list of possible headache treatments, but does not mean that treatment must be hormonal. Table 2 lists nonhormonal therapies that have been investigated specifically for the treatment of hormonally associated headaches. A number of these are drugs that already have FDA approval for a headache, pain or migraine indication, and for which there is a great deal of existing safety and efficacy information and clinical experience. Nonetheless, interventions for hormonal headaches that directly target the presumed hormonal trigger, rather than working on downstream events, have a powerful intellectual and emotional appeal for doctors and patients. Many women with migraine need or choose to use hormonal treatment for other conditions or for contraception, and for them hormonal treatment of migraine may be desirable. Finally, some women do not benefit from or cannot use nonhormonal treatment strategies for migraine, and trials of hormonal treatments may be defensible.

The overarching goal of all hormonal treatment regimens for migraine is minimization of estrogen fluctuations. In the case of migraine associated with menstruation in pre or peri-menopausal women, several treatment strategies are possible. Supplemental estrogen may be administered in the late luteal phase of the natural menstrual cycle or during the pill-free week of traditional combination oral contraceptives. Modified contraceptive regimens may be used that extend the duration of active hormone use, minimize the duration or extent of hormone withdrawal, or both. Some treatment regimens use drugs that eliminate ovarian cycling, with or without add-back estrogen, while others employ anti-estrogen drugs. In menopause, hormonally associated migraine is most likely to be due to estrogen-replacement regimens, and treatment generally involves manipulating these regimens.

About khorrami4

I am a assistant professor of physiology
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