Dr Kalidas is Assistant Professor, Department of Neurology, and Director, Division of Headache Medicine, University of South Florida, Tampa, Florida.

Kavita Kalidas, MD

Headache is among the most common neurological conditions with a current worldwide prevalence in the general population of 47%.

 The Global Burden of Disease Study 2015 ranks headache disorders (migraine, tension type headache, and medication overuse headache) as the third leading cause of life lost to disability worldwide in the 15- to-49 age group.

 Women have more frequent headaches, in part because of the higher prevalence of migraines in them (18%) compared to men (6%).

 Hormonal fluctuations during adolescence, pregnancy, and menopause, as well as use of oral contraceptive (OC) pills and postmenopausal hormone therapy are known to impact migraine frequency and intensity throughout a woman’s lifetime. This article reviews how migraines in women are impacted by the fluctuating hormone levels they experience throughout their lifecycle.

Migraine is characterized as recurrent moderate to severe headache made worse with activity and associated with sensitivity to light, sound, nausea and vomiting.

 Approximately 1 in 4 migraineurs have aura, which are fully reversible visual, sensory, or speech symptoms lasting between 5 and 60 minutes prior to onset of head pain. Visual symptoms are most common and may include either loss of vision or additional symptoms such as lights, lines spreading peripherally, or a combination of loss of vision and additional symptoms. Sensory symptoms include spreading numbness or tingling and speech disturbances such as word-finding difficulties.

Migraine is considered an inherited neurovascular disorder in which activation of the trigeminovascular pain pathway results in release of neuro peptides such as calcitonin gene-related peptide and substance P.

 Changes in levels of serotonin, estrogen, progesterone, melatonin and nitric oxide also influence the occurrence of migraine. Concerning features in evaluation of headache disorders that necessitate neuroimaging with magnetic resonance imaging of the brain include a significant change in attack frequency or severity and new clinical features such as changes in vision, speech, weakness, numbness, and tingling (Table 1). Other concerning features include a sudden, abrupt and quickly escalating headache, impaired alertness, confusion, and presence of systemic symptoms and secondary headache risk factors such as fever, weight loss, cancer, or retroviral disease.

Menstrual migraines can be divided into 2 categories: pure menstrual migraine and menstrually related migraine (Table 2). About 14% of women have pure menstrual migraine, which is migraine only in association with menses with no other episodes of it throughout the month. In contrast, menstrually related migraine occurs in about 60% of women and is defined as migraines that occur consistently during the menstrual cycle in a patient who also has migraines with nonhormonal triggers throughout the month.

 The International Classification of Headache Disorders 3 Beta defines menstrual migraine as occurring from 2 days prior to onset of menses until 3 days after onset of menses.

Menstrual migraine is thought to occur due to the abrupt drop in estrogen that occurs with menses each month, which is further supported through studies showing that perimenstrual treatment with estrogen can prevent development of menstrual migraine but not menses.

 Menstrual migraines typically are not associated with aura, are associated with more disability and more severe, and they usually are more resistant to treatment.

 Nonsteroidal anti-inflammatory drugs (NSAIDs), triptans-5HT

 agonists that are US Food and Drug Administration (FDA)-approved for acute treatment of migraine - dihydroergotamine, combination analgesics (acetaminophen, aspirin, caffeine), and antiemetics (prochlorperazine, promethazine, metoclopramide) can be used acutely to manage migraine-related pain, photophobia, phonophobia, nausea, and vomiting.

 The goal of acute treatment is pain freedom in 2 hours and control of associated symptoms of nausea, vomiting, photophobia, and phonophobia.

When migraine frequency is greater than 6 days per month, daily preventative agents should be considered, such as propranolol, topiramate and valproate, to decrease both the number and the intensity of acute escalations.

 For women who have regular menstrual cycles with significant disability associated with menstrual migraine, short-term prophylaxis or mini-prophylaxis should be considered. The goal of short-term prophylaxis is decreasing duration, frequency, intensity, and disability of menstrual migraine. Options include using NSAIDs (naproxen) or triptans (frovatriptan, naratriptan, zolmitriptan) daily starting 2 to 3 days prior to onset of menses up to 3 to 7 days post-onset of menses. There is Level A evidence for use of Frovatriptan and Level B evidence for use of naratriptan and zolmitriptan (Table 3). Adverse effects associated with use triptans for short-term prophylaxis are similar to those seen with use of these drugs for acute treatment. Hormonal treatments can alter the menstrual cycle and, therefore, occurrence of menstrual migraines. Level C evidence exists for estradiol gel 1.5 mg or an estrogen patch used for 7 days starting from 2 to 5 days prior to onset of menses to maintain the estradiol level and prevent the estrogen drop that triggers menstrual migraine.

 Another approach is to use combined hormonal contraceptive pills continuously, eliminating placebo pills for 3 consecutive packs and eliminating menses once every 3 months. During the weeks when placebo pills are taken, patients can then be placed on short-term migraine prophylaxis. Irregular bleeding may be a complication of this protocol.

 Identifying the role that monthly hormonal fluctuations play in a patient’s headache pattern and targeting treatment to that pattern can significantly improve menstrual migraine control.

Management of migraine in pregnancy remains challenging because the goal is to decrease migraine-related disability and prevent fetal exposure to potentially teratogenic medications. The majority of women, up to 60%, will experience a decrease in migraine frequency during pregnancy.

 The most significant improvement in frequency is seen in women who have menstrual migraine. In some women, migraine frequency increases during the first trimester, but increasing levels of estrogen and absence of hormonal fluctuations are credited for decreased migraine frequency in the second and third trimesters.

 Patients with migraine with aura are less likely to notice a decrease in frequency.

 New-onset migraine in pregnancy – occurring in up to 7% of pregnancies – usually occurs during the first trimester and most often with aura.

 Women who continue to experience migraine attacks throughout pregnancy may require treatment but it is important to remember that not all medications used for migraine are safe in pregnancy.

Acetaminophen, which is FDA category B, is the medication of choice for headache in pregnancy but it’s efficacy in migraine remains limited. NSAIDS can also be used under certain circumstances, though their use in the first and third trimesters is associated with specific risks and contraindications including oligohydramnios, premature closure of the ductus arteriosis, and bleeding complications. Triptans remain FDA category C, meaning that risk to humans has not been ruled out. The Sumatriptan, Naratriptan, and Treximet Pregnancy Registry, which included 528 outcomes of exposure in the first trimester to sumatriptan, detected no signal of teratogenicity associated with major birth defects.15 Although these data are reassuring, no triptan registries with large-scale sample populations are available.

Opiates carry a category B rating and may be used during pregnancy, but frequent use is associated with concern for rebound headaches and dependence. Antiemetics, diphenhydramine, and corticosteroids are considered safe and may be effective for acute management of migraine. For women with high-frequency migraine who require daily prevention, memantine and cyproheptadine are considered Category B, and amitriptyline and beta blockers are considered Category C (Table 4).

 Current standard references such as those available via the FDA, the American Academy of Pediatrics, and Hale’s reference Medications and Mother’s milk should be consulted for current recommendations. (The FDA has determined that use of letter categories for drugs will be abolished and each drug will have a list of known and unknown risk findings. For the purposes of ease of communication in this article these categories were maintained.)

Migraines should be considered a potential risk factor in obstetrics because there is increasing evidence that migraine is a risk factor for vascular complications during pregnancy, including gestational hypertension and preeclampsia, stroke, myocardial infarction, and venous thromboembolism.

 Further research is warranted to understand the mechanisms underlying increased risk of vascular disease in pregnant migraineurs.

Fluctuating hormone levels during the transition to menopause can result in an increase in migraine frequency and disability. Research suggests that women who are predisposed to migraine due to fluctuating hormone levels, such as those who have a history of menstrually related migraine, pure menstrual migraine, onset of migraine with pregnancy or contraceptive use, are more likely to have worsening of migraine in perimenopause.

 Unlike perimenopause, during which hormone fluctuations are significant, menopause is characterized by hormonal stability due to decline in production of estrogen and progesterone, which results in a decrease in frequency, intensity, and disability associated with migraine.

 Studies suggest that 62% of prior headache sufferers report a decrease in headache post-menopause and only 14% of menopausal women report having headaches.

 Characteristics of women who experience migraine in menopause are a younger age at menopause, have a history of surgical menopause, and regular use of cigarette or daily use of alcohol.

 Previous use of combined hormonal contraceptives (CHCs) and current use of hormonal therapy also increase risk of postmenopausal migraine.

Management of postmenopausal migraine includes use of low-dose hormones. If used continuously, these drugs typically do not increase migraine frequency but the effect of post-menopausal hormone therapy on migraine is unpredictable. In patients who are particularly sensitive to exogenous hormones, postmenopausal hormone therapy may increase migraine frequency. Transdermal preparations have been shown to be less likely to exacerbate migraine.

 Preventative medications such as beta blockers, calcium channel blockers, topiramate, or valproate should be used for women who have frequent migraine episodes whereas acute treatments such as NSAIDs, triptans, and combination analgesics should be optimized with the goal of pain freedom in 2 hours. Comorbid conditions should be considered when using both preventative and acute treatment so that triptans and erogotamines are avoided in patients who have hypertension and heart disease.

There remains a clear concern regarding use of CHCs, migraine, and stroke. Although the absolute risk of stroke across the overall migraine population is relatively low, it is well defined and increased in women who have a high frequency of migraine with aura, are older than age 35, or who use OCs and smoke.

 Women with migraine with aura have a 1.5 times higher risk of ischemic stroke; women with migraine with aura who smoke and use OCs have a 7.0 times higher risk of stroke.

The relationship between CHC use and stroke appears to be dose-dependent, with pills containing more than 50 mcg of estrogen conferring the greatest risk.

 The American College of Obstetricians and Gynecologists recommends that clinicians consider use of progestin-only pills (POPs), intrauterine or barrier contraceptives for women who have migraine with aura, those who smoke and who are age 35 or older.

 Use of POPs, implants, depot medroxyprogesterone acetate, and the progestin intrauterine device do not result in an increased risk of stroke and they are considered to be safe in women with migraines.

 The copper intrauterine device also is considered safe for women with migraines.

 Migraine without aura appears to have a minimal effect on ischemic stroke risk so CHCs are a contraceptive option for women with migraine without aura.

Migraines in women are impacted by the hormonal fluctuations they experience throughout their lives. Menstrual migraines, pregnancy-related headache and the impact of menopause on migraine all support the role of hormonal changes in migraine frequency and explain the increased frequency of migraine in women in general. Management of migraine throughout a woman’s life should consider hormonal milestones and factors, which at times may require hormonal manipulation in addition to optimizing abortive, preventative and alternative treatments. Recognizing hormonal triggers allows for optimizing the treatment plan to more effectively control migraine, which is the ultimate goal of treatment.

: Dr Kalidas reports that she is on the Speakers Bureau for Allergan, Pernix, Depomed, and Avanir.

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Articles

This article reviews how migraines in women are impacted by the fluctuating hormone levels they experience throughout their lifecycle.

Kavita Kalidas, MD

Articles

Migraines in Women