Migraine in women: the role of hormones and their impact on vascular diseases

Migraine is a predominantly female disorder. Menarche, menstruation, pregnancy, and menopause, and also the use of hormonal contraceptives and hormone replacement treatment may influence migraine occurrence. Migraine usually starts after menarche, occurs more frequently in the days just before or during menstruation, and ameliorates during pregnancy and menopause. Those variations are mediated by fluctuation of estrogen levels through their influence on cellular excitability or cerebral vasculature. Moreover, administration of exogenous hormones may cause worsening of migraine as may expose migrainous women to an increased risk of vascular disease. In fact, migraine with aura represents a risk factor for stroke, cardiac disease, and vascular mortality. Studies have shown that administration of combined oral contraceptives to migraineurs may further increase the risk for ischemic stroke. Consequently, in women suffering from migraine with aura caution should be deserved when prescribing combined oral contraceptives.     

Estrogen and Migraine: Correlations and Prevention

Migraine is a neurovascular condition that is influenced by the hormonal milieu. The risk of a migraine attack is increased among women migraineurs during a 5-day perimenstrual window that starts 2 days before the onset of menses and continues through the first 3 days of menstruation. Evidence suggests that the increased risk results from estrogen withdrawal in the concurrent late luteal/early follicular phase. For some women with menstrual migraine, headaches that occur at this time are more severe, are of longer duration, and are more disabling. If patients have regular menses, short-term prevention strategies may provide relief for women whose headaches are not responsive to acute treatment. Clinical trials designed to assess short-term prevention with estrogen supplements and with triptans have demonstrated efficacy in this setting and have provided new insights into the mechanisms underlying menstrual migraine. This review will summarize the implications of these data for the treatment of women with menstrual migraine.     

Migraine Without Aura and Reproductive Life Events: A Clinical Epidemiological Study in 1300 Women

SYNOPSIS
A retrospective study was conducted on 1300 women suffering from migraine without aura referred to the Headache Centers of Parma and Pavia from 1984 to 1990. All the data concerning their reproductive life, and the modifications induced by it on the course of headache were obtained from record-charts. Migraine frequently started at menarche (10.7%); in 60% of cases the migraine attacks occurred mostly or exclusively in the perimenstrual period, in 67% of cases disappeared during pregnancy, and in 24.1% significantly (P<0.0001) worsened with "pill" intake. This study also designated a migraine subgroup which is more influenced by changes in sexual hormones, i.e. migraine with onset at menarche. This form of migraine shows more frequently a menstrual periodicity, and usually improves during pregnancy. Furthermore, menstrual migraine patients show social and cultural characteristics which distinguish them from other women.     

Migraine headache in perimenopausal and menopausal women

Perimenopause marks a time of change in a woman’s hormonal environment, which is apparent from the resultant irregular periods and vasomotor symptoms. These symptoms can start in the early 40s and continue through to the early 50s. Migraine is also affected by hormonal fluctuations, particularly the natural decline in estrogen in the late luteal phase of the menstrual cycle. This effect of estrogen “withdrawal” on migraine appears to become more predominant during perimenopause. Despite the increased prevalence of headache and migraine in women in their 40s, migraine is underdiagnosed in this population. In women attending with symptoms suggestive of perimenopause, it is important to ask about headache symptoms. Once diagnosed, a number of strategies can be used to manage both perimenopausal migraine and menopausal symptoms effectively, with the potential to reduce the associated morbidity.     

Menstrual Migraine: Pathophysiology, Diagnosis, and Impact

The incidence of migraine varies over the course of the menstrual cycle. In the general population, approximately 60% of women with migraine report an increased frequency of headache during menses. The estrogen withdrawal that occurs just prior to the onset of menses and that leads to loss of serotonergic tone is thought to be the trigger for headaches that arise at this time of the menstrual cycle. The ability of triptans, specific serotonin receptor agonists, to prevent menstrual migraine is consistent with this hypothesis. Moreover, compared with headaches that occur during other times in the cycle, menstrual migraines are more severe in most women and may be of longer duration, as well as more resistant to treatment in a subset of women.     

Hormonal factors in migraine: a population-based study of women aged 40 to 74 years

OBJECTIVE: This study investigated some of the relationships between migraine and hormonal factors. METHODS: A neurologist clinically assessed 728 women aged 40 to 74 years attending a population-based mammography screening program. Headache criteria proposed by the International Headache Society were used. Data on hormonal factors were obtained by interview and questionnaire. RESULTS: Twenty-one percent of women with migraine without aura and 4% of women with migraine with aura reported that they experienced >/=75% of their attacks within -2 to +3 days of the menstrual cycle. During pregnancy, women experienced less frequent or less intense attacks of migraine without aura and migraine with aura. A small but significant proportion (12%, P =.04) of women with migraine without aura also had premenstrual disorder. Associations between migraine and menarche, pregnancy, pregnancy-related complications, and menopausal complaints were generally weak and insignificant. Migraine with aura was not related to menopause. A crude odds ratio of 0.47 (95% confidence interval [CI] 0.24-0.86) indicated a decrease in risk for migraine without aura in postmenopausal women. However, after adjusting for differences in age and the use of hormonal replacement therapy, this association was not statistically significant. Time since menopause was a significant factor for migraine without aura in postmenopausal women. CONCLUSION: Although many women with migraine reported a close relationship between their attacks and menses, and relief during pregnancy, the cross-sectional associations between migraine and menopause and menopausal complaints were insignificant.     

Migraine Throughout the Female Reproductive Life Cycle

By the end of their reproductive life cycle, roughly 40% of women have experienced migraine. Women have certain times of vulnerability for migraine that relate to abrupt declines in estrogen levels. Specifically, the prevalence of migraine is higher after menarche, during menstruation, during the postpartum period, and during perimenopause, but it is commonly lower during the second and third trimesters of pregnancy and the postmenopausal years. Therapeutic strategies for migraine management include hormonal manipulation aimed at eliminating or minimizing the decreases in estrogen that trigger the especially severe menstrual-related attacks. This article reviews special considerations for triptan use in pregnant and lactating women and in women with high risk for cardiovascular disease. Health care professionals caring for women throughout their life span should be aware of these important sex-based differences in migraine and migraine management.     

Migraine and hormones: what can we be certain of?

Women suffer from migraine far more frequently than men. This sex difference during the reproductive years is considered to result from additional trigger factors, such as the fluctuating hormones of the menstrual cycle and with the reproductive milestones of women. The role of the female hormones on migraine is illustrated by the phenomenon of menstrual migraine, and the changes in the clinical course of migraine with menarche, pregnancy, menopause and the external application of hormones. In summary, epidemiological, clinical and experimental studies document a substantial influence of female sex hormones on the pathophysiology of migraine headache.     

Migräne und Hormone: Was ist gesichert?

Women suffer from migraine far more frequently than men. This sex difference during the reproductive years is considered to result from additional trigger factors, such as the fluctuating hormones of the menstrual cycle and with the reproductive milestones of women. The role of the female hormones on migraine is illustrated by the phenomenon of menstrual migraine, and the changes in the clinical course of migraine with menarche, pregnancy, menopause and the external application of hormones. In summary, epidemiological, clinical and experimental studies document a substantial influence of female sex hormones on the pathophysiology of migraine headache.     

Hormonal management of migraine associated with menses and the menopause: a clinical review

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.     

Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis--part 2

Migraine headache is strongly influenced by reproductive events that occur throughout the lifespan of women. Each of these reproductive events has a different "hormonal milieu," which might modulate the clinical course of migraine headache. Estrogen and progesterone can be preventative or provocative for migraine headache under different circumstances depending on their absolute serum levels, constancy of exposure, and types of estrogen/progesterone derivatives. Attacks of migraine with and without aura respond differently to changes in ovarian hormones. Clearly a greater knowledge of ovarian hormones and their effect on migraine is essential to a greater understanding of the mechanisms and pathogenesis of migraine headache.     

Migraine and menstruation: a pilot study

OBJECTIVE: To define the term "menstrual" migraine and to determine the prevalence of "menstrual" migraine in women attending the City of London Migraine Clinic. DESIGN: Women attending the clinic were asked to keep a record of their migraine attacks and menstrual periods for at least 3 complete menstrual cycles. RESULTS: Fifty-five women completed the study. "Menstrual" migraine was defined as "migraine attacks which occur regularly on or between days -2 to +3 of the menstrual cycle and at no other time". Using this criterion, 4 (7.2%) of the women in our population had "menstrual" migraine. All 4 women had migraine without aura. A further 19 (34.5%) had an increased number of attacks at the time of menstruation in addition to attacks at other times of the cycle. Eighteen (32.7%) had attacks occurring throughout the cycle but with no increase in number at the time of menstruation. Fourteen (25.5%) had no attacks within the defined period during the 3 cycles studied. DISCUSSION: A small percentage of women have attacks only occurring at the time of menstruation, which can be defined as true "menstrual" migraine. This group is most likely to respond to hormonal treatment. The group of 34.5% who have an increased number of attacks at the time of menstruation in addition to attacks at other times of the month could be defined as having "menstrually related" migraine and might well respond to hormonal therapy. The 32.7% who have attacks throughout the menstrual cycle without an increase at menstruation are unlikely to respond to hormonal therapy. The 25.5% who do not have attacks related to menstruation almost certainly will not respond to hormonal therapy.     

Medical oophorectomy with and without estrogen add-back therapy in the prevention of migraine headache

OBJECTIVES: To determine the preventive benefit of "medical oophorectomy" and transdermal estradiol in women with migraine. BACKGROUND: Epidemiological studies have demonstrated that declines in serum estrogen levels occurring during normal menstrual cycles can trigger headache in women with migraine. Prior to this study, no randomized controlled trials have evaluated whether minimizing these hormonal changes pharmacologically can prevent headache. METHODS: Twenty-one women with regular menstrual cycles and a diagnosis of migraine headache were enrolled. After a 2.5-month placebo run-in phase, all patients received a subcutaneous goserelin implant (a gonadotropin-releasing hormone agonist) to induce a medical oophorectomy. One month later, while continuing goserelin, participants were randomized to receive a transdermal patch containing 100 microg of estradiol-17beta (gonadotropin-releasing hormone agonist/estradiol group, n = 9) or a placebo patch (gonadotropin-releasing hormone agonist/placebo group, n = 12) during a 2-month treatment phase. The primary outcome measure was the headache index, which was defined as the mean of pain severity ratings (0 to 10 scale) recorded three times per day by daily diary. Secondary outcome measures included headache disability, headache severity, headache frequency, and the percentage of headaches with a pain severity rating of 7 or greater. RESULTS: The headache index was significantly lower during the treatment period in the gonadotropin-releasing hormone agonist/estradiol group than in the gonadotropin-releasing hormone agonist/placebo group (P =.025). Similar improvements were observed in the gonadotropin-releasing hormone agonist/estradiol group for all secondary outcome measures with the exception of headache frequency, which was unchanged between the groups. Within the gonadotropin-releasing hormone agonist/estradiol group, there was a 33.7% reduction (95% confidence interval, -64.4 to -3.0) in the headache index during the treatment phase when compared with the placebo run-in phase; no difference was seen between those phases within the gonadotropin-releasing hormone agonist/placebo group. CONCLUSIONS: Minimization of hormonal fluctuations with gonadotropin-releasing hormone agonist therapy alone is inadequate to prevent headache in women who are premenopausal with migraine. The addition of transdermal estradiol to existing gonadotropin-releasing hormone agonist therapy provides a modest preventive benefit.     

The impact of extended-cycle vaginal ring contraception on migraine aura: a retrospective case series

Objective.— To determine whether extended‐cycle dosing of an ultralow dose vaginal ring contraceptive decreases frequency of migraine aura and prevents menstrual related migraine (MRM). Background.— Many women are denied therapy with combined hormonal contraceptives due to published guidelines that recommend against their use in migraine with aura (MwA). The concern is that these products might further elevate the risk of ischemic stroke that accompanies aura. Stroke risk has been reported to vary directly with aura frequency, and aura frequency in turn has been shown to have a direct relationship to estrogen concentration. With the evolution of increasingly lower dosed combined hormonal contraceptives, we now have formulations that – provided that ovulation is inhibited – result in lower peak levels of estrogen than the concentrations attained during the native menstrual cycle. These formulations would thus be expected to result in a lower frequency of migraine aura. Furthermore, as extended‐cycle therapy eliminates monthly estrogen withdrawals, this therapy would likewise be expected to prevent MRM. Methods.— This pilot study is an institutional review board‐approved retrospective database review. We queried our database of 830 women seen in a subspecialty menstrual migraine clinic to identify women who met all inclusion criteria: (1) current history of MwA; (2) confirmed diagnosis of MRM; and (3) treatment with extended‐cycle dosing of a transvaginal ring contraceptive containing 0.120 mg etonogestrel/15 µg ethinyl estradiol. Standardized calendars that specifically document bleeding patterns, headache details, and occurrence of aura are required of all patients in this clinic. Results.— Twenty‐eight women met study criteria, none of whom were smokers. Of these, 5 discontinued use of etonogestrel/ethinyl estradiol within the first month, leaving 23 evaluable subjects. At baseline, subjects averaged 3.23 migraine auras/month (range: 0.1‐12). With extended dosing of the vaginal ring contraceptive, median frequency was reduced to 0.23 auras per month following treatment after a mean observation of 7.8 months (P < .0005). No subject reported an increase in aura frequency. On this regimen, MRM was eliminated in 91.3% of the evaluable subjects. Conclusion.— In this sample of women with both MwA and MRM, use of an extended‐cycle vaginal ring contraceptive was associated with a reduced frequency of migraine aura and with resolution of MRM. This cannot be extrapolated to suggest that stroke risk in MwA will be similarly reduced. Studies to evaluate this relationship are warranted.     

Management of Menstrual Migraine: A Review of Current Abortive and Prophylactic Therapies

After menarche, women have an increased prevalence of migraine compared to men. There is significant variability in the frequency and severity of migraine throughout the menstrual cycle. Women report migraines occur more frequently during menses, and that those are more severe than other migraines. This creates a unique challenge of effectively treating menstrually related and pure menstrual migraines. As with treatment of other migraines, both abortive and prophylactic treatment regimens are used. Triptans demonstrate efficacy in the abortive management of menstrually related and pure menstrual migraines. For migraines that occur primarily during menses or that are particularly resistant to other therapies, intermittent prophylactic therapies can be used. Naproxen and estrogens have been studied for this use. More recently, triptans have been examined and have shown efficacy for intermittent prophylaxis of menstrual migraine.     

Contraception and Headache

Most women have used at least 1 method of contraception during their reproductive years, with the majority favoring combined oral contraceptives. Women are often concerned about the safety of their method of choice and also ask about likely effects on their pre‐existing headache or migraine and restrictions on using their headache medication. While there should be no restriction to the use of combined hormonal contraceptives by women with migraine without aura, the balance of risks vs benefits for women with aura are debatable. Migraine with aura, but not migraine without aura, is associated with a twofold increased risk of ischemic stroke, although the absolute risk is very low in healthy, nonsmoking women. Although ethinylestradiol has been associated with increased risk of ischemic stroke, the risk is dose‐dependent. Low‐dose pills currently used are considerably safer than pills containing higher doses of ethinylestradiol but they are not risk‐free. This review examines the evidence available regarding the effect that different methods of contraception have on headache and migraine and identifies strategies available to minimize risk and to manage specific triggers such as estrogen “withdrawal” headache and migraine associated with combined hormonal contraceptives. The independent risks of ischemic stroke associated with migraine and with hormonal contraceptives are reviewed, and guidelines for use of contraception by women with migraine are discussed in light of the current evidence.     

Physiology of the menstrual cycle

The normal female life cycle is associated with a number of hormonal milestones: menarche, pregnancy, contraceptive use, menopause, and the use of replacement sex hormones. All these events and interventions alter the levels and cycling of sex hormones and may cause a change in the prevalence or intensity of headache. The menstrual cycle is the result of a carefully orchestrated sequence of interactions among the hypothalamus, pituitary, ovary, and endometrium, with the sex hormones acting as modulators and effectors at each level. Oestrogen and progestins have potent effects on central serotonergic and opioid neurons, modulating both neuronal activity and receptor density. The primary trigger of menstrual migraine appears to be the withdrawal of oestrogen rather than the maintenance of sustained high or low oestrogen levels. However, changes in the sustained oestrogen levels with pregnancy (increased) and menopause (decreased) appear to affect headaches. Headaches that occur with premenstrual syndrome appear to be centrally generated, involving the inherent rhythm of CNS neurons, including perhaps the serotonergic pain-modulating systems.     

Pain perception and laser evoked potentials during menstrual cycle in migraine

The association between estrogens “withdrawal” and attacks of migraine without aura is well-known. The aim of the study was to examine the features of laser evoked potentials (LEPs), including habituation, in women suffering from migraine without aura versus healthy controls, during the pre-menstrual and late luteal phases. Nine migraine without aura and 10 non-migraine healthy women, were evaluated during the pre-menstrual phase and late luteal phase. The LEPs were recorded during the inter-critical phase. The right supraorbital zone and the dorsum of the right hand were stimulated. Three consecutive series of 20 laser stimuli were obtained for each stimulation site. Laser pain perception was rated by a 0–100 VAS after each stimulation series. Migraine patients exhibited increased LEPs amplitude and reduced habituation compared to normal subjects. Laser-pain perception was increased during the pre-menstrual phase in both patients and controls. Migraine patients and controls showed increased P2 and N2–P2 amplitude in the pre-menstrual phase, on both stimulation sites. During the pre-menstrual phase the N2–P2 habituation appeared to be reduced in both migraine and healthy women. The estrogen withdrawal occurring during the menstrual cycle may favor reduced habituation of nociceptive cortex, which may facilitate pain symptoms and migraine in predisposed women.     

Prevention of migraine in women throughout the life span

Migraine is a common disorder in women. The 1-year prevalence of migraine is 18% in women compared with 6% in men. Migraine most commonly occurs during the reproductive years, affecting 27% of women 30 to 49 years of age. The predominance of this disorder and its social, functional, and economic consequences make migraine an important issue in women's health. The hormonal milieu has a substantial effect on migraine in women. An understanding of these hormonal influences in the various stages of life in females is essential to the management and prevention of migraines. This article reviews migraine prevention strategies with an emphasis on specific therapies for each stage of a woman's life.