Chronic Conditions and Menopause

Migraine, menopause and hormone replacement therapy

Post Reproductive Health 0(0) 1–8 ! The Author(s) 2017 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/2053369117731172 journals.sagepub.com/home/prh

E Anne MacGregor

Abstract Perimenopause marks a period of increased migraine prevalence in women and many women also report troublesome vasomotor symptoms. Migraine is affected by fluctuating estrogen levels with evidence to support estrogen ‘withdrawal’ as a trigger of menstrual attacks of migraine without aura, while high estrogen levels can trigger migraine aura. Maintaining a stable estrogen environment with estrogen replacement can benefit estrogen-withdrawal migraine particularly in women who would also benefit from relief of vasomotor symptoms. In contrast to contraceptive doses of ethinylestradiol, migraine aura does not contraindicate use of physiological doses of natural estrogen. In women with migraine with or without aura, using only the lowest doses of transdermal estrogen necessary to control vasomotor symptoms minimizes the risk of unwanted side effects. Cyclical progestogens can have an adverse effect on migraine so continuous progestogens, as provided by the levonorgestrel intrauterine system or in continuous combined transdermal preparation, are preferred. There are no data on the effect of micronized progesterone on migraine, either cyclical or continuous. Non-hormonal options for both conditions are limited but there is evidence of efficacy for escitalopram and venflaxine.

Keywords Estrogen, hormone replacement therapy, menopause, migraine, vasomotor symptoms

Introduction Migraine is a common episodic primary headache disorder. Although migraine affects both sexes, it is predominantly a female disorder, with a cumulative lifetime incidence of 43% in women and 18% in men.1 These sex differences are generally attributed to the differential effects of male and female sex hormones on migraine pathophysiology. Notably, migraine prevalence is very similar in children but following puberty the prevalence increases more in women than in men reaching a three-fold difference in the prevalence ratio during the fourth decade.2 Perimenopause marks a further increased risk of migraine, evidenced by a bimodal rate of change of prevalence (Figure 1).3 In studies of women attending menopause clinics, between one-quarter and one-third had migraine, of which the majority reported severe attacks occurring more often than once a month.4,5 Despite significant disability, migraine is often underreported by patients and underdiagnosed by healthcare professionals.6 Migraine without aura is the most prevalent type of migraine, the main symptoms of which are headache associated with nausea and/or vomiting, photophobia and phonophobia.7 Untreated or unsuccessfully treated

attacks last from 4 to 72 h and, particularly if severe, may require bed-rest. Migraine with aura, in which the headache is preceded by transient and fully reversible neurological symptoms, is less common affecting around one in four people with migraine. Migraine aura without headache affects only one in one hundred people with migraine. Types of migraine are not mutually exclusive and the prevalence of each type changes with age, with attacks of migraine aura without headache more common in later life following on from an earlier history of migraine with or without aura. This review includes simple diagnostic tools for migraine and an overview of the effects of perimenopause and hormone therapy on migraine, to give healthcare providers a better understanding of how to combine safe and effective management of

Barts Sexual Health Centre, London, UK Corresponding author: E Anne MacGregor, Barts Sexual Health Centre, St Bartholomew’s Hospital, London EC1A 7BE, UK. Email: [email protected]

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Post Reproductive Health 0(0) Box 1. ‘PIN’ the diagnosis of migraine without aura with IDMigraineTM 8,9 Photophobia Impairment Nausea

Figure 1. The rate of change (first derivatives) in prevalence over the age continuum in females. *The horizontal line at 0 on the y-axis indicates no change (i.e. acceleration or deceleration) in the rate. yDuring childhood and early adolescence, the rate is accelerating quickly. zRate begins to slow its acceleration. §Rate is decelerating. Reproduced from Victor et al.,3 by permission of SAGE Publications.

vasomotor symptoms with safe and effective management of migraine.

Diagnosing migraine The International Headache Society (IHS) has published a classification and diagnostic criteria for migraine and other headache disorders, now in its third edition.7 These criteria are important to ensure homogeneity in clinical trials but are not always practical for use in the clinical setting. Migraine can more simply be considered as recurrent episodes of disabling headache, lasting 4–72 h associated with nausea and photophobia in an otherwise well person. I-D Migraine is a validated diagnostic screening tool based on these key features (Box 1).8,9 In a primary care setting I-D Migraine had a sensitivity of 81% and a specificity of 75% relative to an IHS-based migraine diagnosis assigned by a headache specialist. Because migraine is a prevalent condition, the positive predictive value was 93%.8 However, I-D Migraine is only a screening tool and given a false positive rate of 19%, a more complete evaluation is necessary following a positive result in order to confirm a diagnosis of migraine. Aura can be more difficult to diagnose as the symptoms are often confused with common premonitory symptoms that precede headache in attacks of both migraine with and without aura (Figure 2).10 Correct diagnosis of aura is important since aura is a marker of an individual at increased risk of ischaemic stroke.11 Key aura features are the duration and timing of symptoms in relation to headache (Box 2).12 Visual aura

Does light bother you when you have a headache? Do you experience headaches that impair your ability to function? Do you feel nauseated or sick to your stomach when you have a headache?

accounts for over 98% of aura symptoms, typically as fortification spectra or a scintillating scotoma starting near the centre of vision and spreading peripherally over 20 to 30 min. Aura usually resolves before the onset of headache, which may be mild or even absent. When asked to describe the symptoms, patients frequently draw a zigzag in the air, representing typical scintillations of migraine aura.13 Sensory symptoms, such as pins and needles or numbness spreading up one arm into the side of the face and mouth, and speech disturbance are less prevalent and almost always accompanied by visual aura. In contrast to these specific features of aura, premonitory symptoms are common before attacks of migraine with and without aura and should not be confused with aura. Premonitory symptoms occur several hours or even up to a couple of days before onset of aura or migraine headache. Visual premonitory symptoms are more vague than aura symptoms and include generalized ‘spots before the eyes’, ‘flashing lights’, blurring of vision or photophobia of variable duration, which often continue during the headache phase.13

Effects of hormonal changes on migraine Throughout the reproductive years, menstruation is one of the most significant risk factors for migraine without aura with the highest incidence of attacks during five days of the cycle, starting two days before menstruation and during the first three days of bleeding.14–16 Research suggests that one of the triggers of menstrual migraine is the natural fall or ‘withdrawal’ of estrogen in the late luteal phase of the menstrual cycle.17 Estrogen ‘withdrawal’ also accounts for the increased incidence of headache and migraine during the hormone free interval of combined hormonal contraception. Migraine with aura has a different hormonal response, with high estrogen states such as pregnancy, combined hormonal contraception or hormone replacement therapy (HRT), associated with an increased incidence of migraine with aura.18–20 During the perimenopause attacks of migraine without aura often become more frequent and severe, partly

MacGregor

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Figure 2. The five stages of a migraine attack. Adapted from Blau,10 by permission of Elsevier.

Box 2. A simple screen for migraine with aura.12

Box 3. Practice points.

Does the patient have visual disturbances that: Start before the headache? Last up to one hour? Resolve before the headache? If the answer to all three questions is ‘yes’ a diagnosis of migraine aura is likely.

 Perimenopausal women with menstrual migraine and no history of migraine aura may benefit from continuous combined hormonal contraception until age 50.  Migraine aura is not a contraindication to use of replacement doses of natural estrogen.  Use the lowest effective dose of non-oral estrogen that controls vasomotor symptoms.  Where progestogen is required, continuous delivery is recommended, with preparations such as:  levonorgestrel intrauterine system.  transdermal norethisterone.  micronised progesterone.  Women with migraine and vasomotor symptoms in whom estrogens are contraindicated may benefit from escitalopram or venlafaxine.

because menstrual periods are more frequent.21 Hyperestrogenism coupled with decreased luteal phase progesterone disrupt the menstrual cycle,22 and are the likely causes of increased morbidity from migraine and other gynaecological disorders that characterize this stage of life. Hence, maintenance of a stable hormonal milieu should be associated with fewer migraine attacks. Accordingly, several studies have used perimenstrual estrogen supplements in women with regular periods in order to maintain mid-luteal levels until the follicular rise in estrogen, successfully preventing menstrual migraine.23 While irregular periods prohibit perimenstrual treatment because of the difficulty of timing, suppression of ovarian activity using estradiol implants, continuous combined hormonal contraception or desogestrel progestogen-only contraceptives, is an option.24–26 Following natural menopause, the prevalence of migraine gradually improves with time, mirroring decline in ovarian function.27,28 Wang et al.29 noted

that the increase before menopause and decline after spontaneous menopause tended to occur only in women with a history of migraine associated with hormonal changes. There are case reports of reduction of migraine following induced medical menopause using gonadotrophin releasing hormone analogues, with and without ‘add-back’ HRT.30–32 It has been suggested that women with severe refractory menstrual migraine who improve on GnRH analogues might benefit from surgically induced menopause and hysterectomy with add-back estrogen.33 However, bilateral oophorectomy

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Table 1. Recommended pharmacological options with evidence of efficacy for management of vasomotor symptoms and prophylaxis of migraine. Treatment Hormonal Post hysterectomy Uterus intact: premenopause Uterus intact: postmenopause

Non-hormonal SSRIs SNRIs

Dose

Continuous transdermal estrogen Continuous transdermal estrogen plus LNG-IUS

Lowest dose of transdermal estrogen required to control vasomotor symptoms

Continuous transdermal estrogen plus LNG-IUS Continuous combined estrogen/progestogen patches Continuous transdermal estrogen plus micronized progesterone Tibolone

2.5 mg/day

Escitalopram Venlafaxine

10–20 mg/day 37.5–150 mg/day

LNG-IUS: levonorgestrel intrauterine system; SSRI: selective serotonin reuptake inhibitor; SNRI: serotonin norepinephrine reuptake inhibitor

performed before natural menopause is associated with several negative outcomes, particularly in women under age 45 years, not all of which may be prevented with estrogen replacement.34 Indeed surgical menopause, even without oophorectomy, appears to be associated with a greater burden of migraine compared to natural menopause.29,35–38 In contrast to migraine without aura, migraine with aura appears to be unaffected by either natural or surgical menopause.28

with HRT use, compared to 22.5% reporting no change, and 13.3% reporting worsening headache.40 Despite the potential negative effects, HRT is often recommended for perimenopausal women with migraine.41 This is not surprising since many women with worsening migraine are also likely to be experiencing vasomotor symptoms. So it is practical to consider how HRT can be optimised to benefit both conditions.

Effect of HRT on migraine

Estrogen. Stable estrogen levels are best achieved using non-oral routes of estradiol administration, which are less likely than oral formulations to have a negative effect on migraine. In an observational study of 50 women followed over seven months, frequency and duration of migraine attacks were unchanged in women using continuous transdermal estradiol 50 mcg plus cyclical medroxyprogesterone acetate (MPA) 10 mg/day.42 However, in women taking continuous oral conjugated estrogens 0.625 mg/day plus cyclical MPA 10 mg/day, there was a significant increase in attack frequency and days with headache. If oral preparations are favoured, one study suggests that tibolone may be the best option. In a six-month observational study comparing a combination of 1 mg estradiol plus 0.5 mg norethisterone acetate daily versus 2.5 mg tibolone daily, tibolone was associated with significantly shorter duration of attacks and significantly less analgesic use, although the frequency of attacks was the same for both groups.43 The dose of estrogen is as important as the route of delivery as too high a dose, coupled with surges of endogenous oestrogen, can trigger migraine aura as well as causing symptoms of estrogen excess including

Few studies have assessed the effect of HRT on migraine and the results are inconsistent. Data from the 1909 women with migraine in the preceding year enrolled into the Women’s Health Study, the odds ratio (OR) of 1.42 (95% CI 1.24–1.62) for women with migraine who were current users of HT compared with never users.38 The ORs were similar for estrogenonly (OR 1.39, 95% CI 1.14–1.69) and combined HRT (OR 1.41, 95% CI 1.22–1.63). There was no difference in risk associated with oral versus transdermal, high versus low estrogen dose, type of progestogen or cyclical versus continuous administration. Similarly, results from a cross-sectional questionnaire of 6007 postmenopausal women showed a significant association between headache and current use of HRT irrespective of whether the route of delivery was local (OR 1.3, 95% CI 1.0–1.6) or systemic (OR 1.3, 95% CI 1.1–1.5).39 In contrast, a study of 120 women attending a headache clinic found that HRT was beneficial for migraine, with 64.1% of women reporting improvement or complete remission of headache associated

Type of hormone

MacGregor nausea, fluid retention, breast tenderness and leg cramps. Kaiser and Meienberg19 reported on 10 women attending an ophthalmology clinic who were using 50 mcg transdermal estrogen patches. Six women had a history of migraine predating use of HRT (three had migraine with aura, three had migraine without aura). All six women reported increased headache severity associated with visual scintillations since starting HRT. A further woman with no history of migraine developed visual scintillations without headache. In all cases, the symptoms resolved following cessation of HRT. However, stopping HRT may not be necessary if aura develops since reducing the estrogen dose and/or changing route of delivery may resolve aura while maintaining efficacy for vasomotor symptom relief.44 Of importance is the need to tailor the dose to the individual as there are large inter- and intra-individual variations in serum estrogen concentrations irrespective of route of administration.45 So for some women, standard doses of estrogen might be more than they require. Further, some postmenopausal women continue to produce significant amounts of estrone and estradiol in extra-ovarian tissue, including the brain.46 Progestogen. Progestogen is a necessary adjunct to estrogen to provide endometrial protection in women with an intact uterus. While the association between cyclical progestogens and perimenstrual symptoms, headaches and migraine has long been recognised,47–49 there are no specific data regarding the effect on migraine of different types, route of delivery or doses of either synthetic progestogens or natural progesterone. Continuous progestogen appears to be better tolerated by migraineurs than cyclical progestogens,50 but most continuous formulations are only licensed for use postmenopause. The levonorgestrel intrauterine system (MirenaÕ ) is the obvious option during the perimenopause, as it provides continuous endometrial protection with minimal systemic effects and may in itself benefit migraine.51 Testosterone. Clinical data, although limited, indicate that methyltestosterone and testosterone implants alone have potential benefit on migraine in women.47,52,53 However, Greenblatt and Bruneteau47 following 85 women over 305 woman-years using varying regimes of testosterone and estradiol implants, alone or in combination, found that the best response was in women using a combination of testosterone and estradiol implants.

Risk of ischaemic stroke Three meta-analyses conclude that in women, migraine with aura is associated with an approximately 2-fold

5 increased risk of ischaemic stroke (RR 2.08, 95% CI 1.13–3.84).54–56 Smoking and use of oral contraception further increase the risk.54,57 The majority of studies have been undertaken in younger people and there are few data on older women. The prospective cohort Women’s Health Study enrolled women over age 45 years at study entry who were free of cardiovascular disease, and followed them for 9–12 years. Of 5125 women with selfreported migraine, only active migraine with aura at baseline, and not a past history, was a risk factor for ischaemic stroke. This association was significantly modified by age (p ¼ 0.01) with the highest association among women younger than 50 years (Hazard Ratio (HR) 6.16, 95% CI 2.34–16.21).58 The prospective cohort Atherosclerosis Risk in Communities (ARIC) study ascertained migraine history by interview in 1993–1995.59 Diagnosis of migraine was based on the International Headache Society diagnostic criteria. The average age of participants was 59 years (range 49–73) and 56% were women. Of 12,758 participants at followup in 2011–2013, 12.6% had migraine (1250 women and 372 men). The incidence rate for ischaemic stroke per 1000 person-years was 4.1 for migraine with aura, 2.07 for migraine without aura, 2.44 for non-migraine headache and 3.02 for no headache. The risk was significant for migraine with aura (adjusted HR 1.67, 95% CI 1.1–2.4) but not for migraine without aura (adjusted HR 1.2, 95% CI 0.8–1.7). While some studies suggest a higher prevalence of stroke risk factors such as hypertension, elevated cholesterol and obesity in people with migraine with aura compared to the rest of the population, other studies have found no association.59–62 In any case, the migraine with aura is an independent risk factor since the risk remains increased when analyses control for other major stroke risk factors.61–63 Only one study has addressed the risk of ischaemic stroke in women with migraine using HRT. The Oxford Vascular Study (OXVASC), a population-based cohort study followed participants over 10 years and assessed the association between migraine and incident cryptogenic TIA and stroke.63 Of the 92,728 participants, 1810 had an incident ischaemic event of which 668 were cryptogenic. While there was a trend towards increased risk of cryptogenic events in current HRT users with migraine, the association was not significant. There were no data on the type, dose, route of delivery, or duration of use of HRT. While oral estrogen replacement is associated with a small increased risk of stroke, transdermal estradiol is associated with minimal, if any, increase in risk of stroke above the woman’s own background risk.64 On this basis, there is no good reason for past or current migraine aura to contraindicate use of non-oral HRT.65

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As in women not using HRT, new onset headache should carefully be evaluated for secondary causes, particularly in women over age 50 years. If aura starts for the first time, transient ischaemic attacks should be excluded. The dose and route of delivery of estrogen replacement should be assessed to provide the lowest effective dose necessary to control menopause symptoms. If aura does not resolve, stop HRT, re-assess, and consider non-hormonal strategies as necessary.

Declaration of conflicting interests

Alternatives to HRT in women with migraine

Sole author.

For women in whom estrogen is contraindicated, there is some evidence to support the efficacy of escitalopram and venlafaxine for control of vasomotor symptoms,65,66 and for migraine prophylaxis.67 As with hormone therapy, initial exacerbation of migraine in the first few weeks of treatment can occur; therefore, it is important not to stop treatment too early.68 Clonidine (50–75 micrograms b.d.) is licensed for menopausal hot flushes and migraine prophylaxis. However, trial data to support its efficacy as a migraine prophylactic are limited.

Conclusions Perimenopause is a time of peak migraine prevalence, particularly perimenstrual attacks of migraine without aura. Perimenopausal women should routinely be asked about headache and migraine so that they can be offered appropriate advice (Box 3, Table 1). However, there is a paucity of research regarding management of migraine in perimenopausal women. Of the limited data available, a stable estrogen environment can benefit migraine, either with appropriate contraceptive hormones to suppress endogenous ovarian activity or with estrogen replacement therapy to maintain constant levels. Non-oral routes of delivery, using the lowest effective dose necessary to control vasomotor symptoms, are associated with the most favourable outcomes. For women with an intact uterus, transdermal estrogen together with the levonorgestrel intrauterine system is appropriate during perimenopause and postmenopause, while continuous combined transdermal HRT is an additional option postmenopause. The presence of migraine aura contraindicates use of contraceptive synthetic estrogens, which are themselves an independent risk factor for ischemic stroke, but does not contraindicate use of physiological doses of transdermal estrogens. There are data to support use of either SSRI escitalopram or the SNRI venlafaxine for both migraine prophylaxis and management of vasomotor symptoms if estrogens are contraindicated.

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author received no financial support for the research, authorship, and/or publication of this article.

Contributorship

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Migraine, menopause and hormone replacement therapy.

Perimenopause marks a period of increased migraine prevalence in women and many women also report troublesome vasomotor symptoms. Migraine is affected...
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