Abstract
Up to 43 per cent of women and 18 per cent of men are affected by migraine at some time in their lives [1]. This sex difference is accounted for by the influence of reproductive hormones in women, with notable effects of menarche, menstruation, pregnancy, lactation, menopause and hormonal contraception on migraine. In particular, the perimenopause is a time of worsening migraine [2–4]. Despite this, migraine is significantly under-reported by women seeking management of menopause who should routinely be asked about headache [4].
Overview
Up to 43 per cent of women and 18 per cent of men are affected by migraine at some time in their lives [1]. This sex difference is accounted for by the influence of reproductive hormones in women, with notable effects of menarche, menstruation, pregnancy, lactation, menopause and hormonal contraception on migraine. In particular, the perimenopause is a time of worsening migraine [2–4]. Despite this, migraine is significantly under-reported by women seeking management of menopause who should routinely be asked about headache [4]. Too often such women are incorrectly advised that menopause hormone therapy (MHT) is contraindicated because of migraine and so do not receive effective treatment.
Migraine
Migraine is simply defined as attacks of moderate to severe headache associated with nausea, photophobia and phonophobia which usually last between 1 and 3 days [5]. It is a fluctuating disorder with periods of remission interspersed by relapse, with women less likely to experience episodes of remission than men [6]. Migraine is a disabling condition, recognized by the World Health Organization to be the second leading cause of years lived with disability (YLDs) in all women and the leading cause in women aged 15–49 years [7].
The two principal types of migraine differ only in their presence or absence of an ‘aura’. About 70–80 per cent of people with migraine experience attacks of migraine without aura (formerly known as common or simple migraine); 10 per cent have migraine with aura (formerly known as classical or focal migraine); fewer than 1 per cent of attacks are aura alone, with no ensuing headache. These phenotypes are not mutually exclusive and 15–20 per cent of people with migraine experience more than one type.
Attacks of episodic migraine occur between once a week and once a year, with a median of one per month, and with complete freedom from symptoms between attacks [8]. There is also an uncommon chronic type affecting around 2 per cent of the population, defined as headache occurring on 15 or more days per month for more than 3 months, which on at least 8 days per month have the features of migraine headache [5].
Diagnosing Migraine
Migraine without Aura
The best predictive symptoms of migraine are throbbing unilateral headache associated with nausea and disability, lasting a day. The presence of these can diagnose migraine with a sensitivity of 95 per cent and a specificity of 78 per cent [9]. These symptoms may be remembered more easily by the mnemonic ‘POUND’, as in ‘pounding headache’ (Table 7.1).
Table 7.1 Screening for migraine headache
| P | Pulsatile quality (headache described as pounding or throbbing) |
| O | One-day duration (episode of headache lasts 4–72 hours if untreated) |
| U | Unilateral location |
| N | Nausea or vomiting |
| D | Disabling intensity (altered usual daily activities during headache episode) |
Note. Three symptoms are predictive for migraine; four symptoms are highly predictive. From [9].
Migraine is commonly misdiagnosed as recurrent sinus headache because of sinus fullness and frontal or facial pressure but a careful history leads to the correct diagnosis [10]. Tension-type headache is sometimes misdiagnosed as migraine but is non-pulsating and typically described by patients as a ‘band-like’ constriction around the head. While mild photophobia or phonophobia may be present with tension-type headaches, they lack the characteristic symptoms of nausea and disability that define migraine.
Menstrual migraine, in which attacks of migraine without aura start on or between 2 days before menstruation and the first 3 days of bleeding, in which the association between migraine and menstruation is greater than chance, affects between 20–60 per cent of women [11].
Aura
Aura is characterized by any combination of visual, hemisensory or language abnormalities, with each symptom developing over at least 5 min and lasting a maximum of 60 min. Visual aura is typically scintillating scotoma, comprising an enlarging blank spot rimmed with a shimmering edge or jagged lines affecting the same hemifield in both eyes, spreading from central to peripheral vision (Figure 7.1) [12]. As the symptoms arise from the visual cortex, they are ‘seen’ even with the eyes closed [13]. Less common are non-visual auras, which include spreading unilateral numbness or tingling spreading up the arm into the face and disturbed thinking or speech. If present, headache usually occurs within one hour of aura symptoms resolving. Because visual aura is the most frequent symptom, its presence can be used to screen for migraine with aura (Table 7.2) [14].
Figure 7.1 Depiction of an expanding scintillating scotoma and fortification spectra by Sir William Richard Gowers [12].
Table 7.2 Screening for typical migraine with aura
| Do you have visual disturbances that … |
| Start before the headache? |
| Last up to one hour? |
| Resolve before onset of headache? |
| Persist with your eyes closed? |
Note. From [14].
Managing Migraine
Effective treatment is dependent on correct diagnosis of migraine [15]. Triggers and predisposing factors should be reviewed and treated appropriately. Simple factors like sleep hygiene, maintaining stable blood sugar levels and avoiding dehydration can easily be managed by lifestyle modification. Diaries are an essential aid to diagnosis and management and can help to identify any associations between migraine, menstruation, menopausal symptoms and MHT.
Symptomatic Treatment
For many women with migraine, effective attack therapy (Table 7.3) and an explanation about the probable cause of worsening migraine are sufficient [16]. Over frequent use of symptom medication, more than 2 days a week, can indicate medication overuse headache requiring drug withdrawal.
| First line | |
| Simple analgesics | Aspirin 900 mg |
| Ibuprofen 400–600 mg | |
| Triptans | Sumatriptan 50–100 mg |
| Second line (if no response to first line) | |
| Other triptans | Almotriptan |
| Eletriptan | |
| Frovatriptan | |
| Naratriptan | |
| Rizatriptan | |
| Zolmitriptan | |
| Triptan plus NSAID combination | Sumatriptan 50–100 mg plus naproxen 500 mg |
| Early or persistent vomiting | |
| Add antiemetic | Metoclopramide 10 mg |
| Prochlorperazine 10 mg | |
| Non-oral formulation of triptan | Intranasal zolmitriptan |
| Subcutaneous sumatriptan | |
Note. Avoid codeine and other opiates. From [16].
Preventive Treatment
If migraine attacks are frequent and/or acute treatment is inadequate, standard prophylactic strategies should be considered (Table 7.4) [16]. Women should be warned that complete response is unlikely; a more reasonable expectation is a 50 per cent reduction in frequency and/or severity of attacks.
| Drug class | Drug example | Route | Target dose |
|---|---|---|---|
| Beta blockers | Propranolol | oral | 80 mg twice daily |
| Antiepileptic | Topiramate | oral | 50 mg twice daily |
| Sodium valproatea | oral | 600 mg twice daily | |
| Tricyclic antidepressant | Amitriptyline | oral | 30–50 mg at night |
| Angiotensin II receptor antagonist | Candesartan | oral | 16 mg daily |
| Calcitonin gene related peptide antagonists | Erenumab | subcutaneous injection | 70–140 mg monthly |
| Fremanezumab | subcutaneous injection | 225 mg monthly or 675 mg three monthly | |
| Galcanezumab | subcutaneous injection | 240 mg first month followed by 120 mg monthly |
Specific management strategies for continuous or perimenstrual prophylaxis are an option for women with a confirmed diagnosis of menstrual migraine. Perimenstrual prophylactic options include non-steroidal anti-inflammatory drugs (NSAIDs), estrogen, or triptans [11]. Hormonal options that inhibit ovarian activity such as continuous combined hormonal contraceptives are useful for women with menstrual migraine without aura needing contraception [11]. The desogestrel progestogen-only pill may be an option for women with migraine aura, but does not fully suppress ovarian activity. Unscheduled bleeding is a common reason for discontinuation [17].
Relationship between Migraine and Menopause
Menopause transition is associated with loss of the regular premenopause hormone cycle as the follicles respond unpredictably to rising FSH resulting in unpredictable swings in hormone levels [18, 19]. Ultimately, the ovaries resist further stimulation and menstruation ceases as estrogen and progesterone levels finally decline [20]. Evidence from several studies supports the clinical impression that these hormone changes parallel an increase in migraine prevalence during perimenopause [2]. Migraine predicts risk of vasomotor symptoms, particularly during late perimenopause, further increasing the burden of disability (Figure 7.2) [21]. Following menopause, migraine prevalence decreases over time, with low estradiol and high FSH levels predictive of lower migraine prevalence [22, 23].
Figure 7.2 Vasomotor symptoms and migraine according to menstrual status. Adjusted mean vasomotor symptoms. Displayed are the mean values predicted by the fixed effects of the model for the migraine groups (control [CTRL] vs migraine [MIG]) at different menstrual status stages for frequency of hot flashes and night sweats. These are covariate adjusted means, specifically means estimated at the grand means of other covariates in the model. Asterisks indicate p < 0.05 (p-values are adjusted for multiple pairwise post hoc tests using the Tukey method). The bar heights represent the average estimated values, and the error bars represent the standard error associated with each estimate. Peri = perimenopause.
Clinical observations indicate that estrogen levels affect migraine without aura and migraine in different ways. Estrogen ‘withdrawal’ migraine, one of the mechanisms associated with menstrual migraine, is almost invariably without aura, even in women who have attacks with aura at other times of the cycle [22]. Women with a history of menstrual migraine may be more vulnerable to exacerbation of migraine during the hormonally unstable perimenopausal period [23].
In contrast, high levels of estrogen as occur during pregnancy, with use of combined hormonal contraception, and with MHT, increase the risk of migraine aura [22]. Estrogen levels across the natural menstrual cycle also affect the phenotype of migraine, with one study finding twice the average levels of estradiol in women with migraine with aura, compared to women with migraine without aura and women without migraine [24].
Few studies have addressed differences in endogenous testosterone levels in women with and without migraine. A case control study of postmenopausal women participating in a mammography screening program matched each of 15 women with migraine to three controls by body mass index and by time since menopause [25]. None of the women were taking estrogen replacement therapy. No statistically significant differences were found in serum levels of androstenedione, total testosterone or free testosterone between women with and without migraine.
However, while hormone fluctuations play a significant role in migraine in women, non-hormonal triggers are still the most important factors initiating migraine attacks, with hormonal factors either being additional or altering the ‘threshold’ to migraine (Figure 7.3) [26]. This is relevant in managing expectations of treatment since, even in women with a strong hormonal pattern of migraine, effectively managing the hormonal trigger is unlikely to eliminate migraine as non-hormonal factors remain unaffected.
Type of Menopause
Improvement in migraine is more likely to occur following spontaneous menopause while surgical menopause can result in worsening migraine [27, 28].
In a cross-sectional study, 1436 Chinese women aged 40–54 years with migraine were classified into five categories of menopausal status: premenopause, early perimenopause, late perimenopause, natural menopause, and surgical menopause [23]. Women were classified as: premenopause if they had regular menstruation; early perimenopause if menstrual cycles were irregular (cycles less than 23 days or more than 35 days) or varied by more than 5 days during the preceding 3 months; late perimenopause if menstrual bleeding had occurred between 3 and 12 months prior to the study; natural menopause if last menstruation was more than 12 months prior to the study; surgical menopause if they had undergone hysterectomy and/or bilateral oophorectomy before natural menopause. The prevalence of migraine was similar in premenopausal and perimenopausal women (16.7 per cent) and lower in the spontaneous menopausal women (10.5 per cent) (OR 0.6; [95 per cent CI 0.4 to 0.9], p = 0.03). Among all menopausal groups, the highest migraine prevalence was seen in women who had had hysterectomies (27 per cent). Low estradiol levels and high FSH levels predicted lower migraine prevalence.
Hysterectomy appears to have an adverse effect on migraine even when the ovaries are retained. A Dutch cross-sectional population questionnaire survey of 986 hysterectomized women with one or both ovaries and 5636 non-hysterectomized women with both ovaries present found that 15.1 per cent of hysterectomized women with ovarian retention reported moderate to severe migraine compared with 8.8 per cent of the non-hysterectomized women (p < 0.001) [29].
Effect of Systemic MHT on Migraine
Two large studies have reported increased prevalence of migraine in women using MHT compared to non-users (Table 7.5) [30, 31]. Both suggest that overall, women using MHT have a higher risk of migraine compared to never-users. Limited data suggest that tibolone has a more favourable effect on migraine than estrogen-progestogen HRT (Table 7.6) [32].
| Study | Study design | Sample size | Migraine prevalence | HRT use | Odds ratio (95% CI) current vs never-users |
|---|---|---|---|---|---|
| Women’s Health Study [30] | Population-based questionnaire | 17 107 postmenopausal women | 11.2% reported migraine headaches within the preceding year, of which 73% fulfilled modified IHS diagnostic criteria for migraine | 38.5% never-users 61.5% current users |
|
| Nord-Trondelag Health Study [31] | Cross-sectional questionnaire | 5507 postmenopausal women | 12.5% never-users, 14.4% past users, 18.3% current (local or systemic) users |
|
|
Note. IHS = International Headache Society.
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