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Migraine and Hormones
Migraine and Hormones Ann Pakalnis, MD This article discusses the role that hormones play in adolescent girls and young women with headaches, which are very common in adolescent girls, in particular, migraine. In many cases, migraine onset may occur shortly around the time of menarche, prevalence of recurrent migraine in this population approaches 15%, and typically the symptoms continue through adulthood. Hormonal changes associated with puberty and the menstrual cycle may significantly influence migraine in young women. This article reviews the following topics: management of menstrually related headaches, changes in ovarian hormones and their relationship to migraine, and oral contraceptives and pregnancy effects on migraine. Semin Pediatr Neurol 23:92-94 C 2016 Elsevier Inc. All rights reserved.
Introduction Ovarian hormones play a significant role in some adolescent girls and young adult women with migraine. Migraine is 3 times more common in adult women than men, and in the adolescent population, migraine is more frequent in girls than boys.1 Migraine headaches among adolescent girls usually tend to begin around the time of menarche.2 During the female reproductive cycle, hormonal changes can influence migraine. The sex hormone axis involves interplay between the hypothalamus, pituitary, and ovaries. Gonadotropin releasing hormone is synthesized in the hypothalamus and binds to receptors in the anterior pituitary gland, which in turn is stimulated to release follicle stimulating hormone (FSH) and luteinizing hormone (LH). Early in the regular 28-day menstrual cycle, FSH and LH induce development of an ovarian follicle that produces estrogen and progesterone. A certain critical increase in estrogen levels leads to a surge in LH levels, which induces ovulation at midcycle. If fertilization does not occur, the luteal phase persists with initially high levels of estrogen and progesterone produced by the ovarian follicle. At the end of the luteal phase, progesterone withdrawal induces menses.3 Fluctuations in estrogen levels influence migraine attacks, with estrogen withdrawal before menses probably being a notable trigger. In adolescent girls and adult women taking combination oral contraceptives (COCs), headaches tend to increase during the placebo week with decreased estrogen From the Departments of Pediatrics and Neurology, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH. Address reprint requests to Ann Pakalnis, MD, Departments of Pediatrics and Neurology, Nationwide Children’s Hospital, The Ohio State University, 700 Children’s Dr, Columbus, OH 43205. E-mail: Ann.pakalnis@ nationwidechildrens.org
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levels present. Estrogen withdrawal also takes place during the postpartum period that is a very vulnerable time for hormonally related migraine headaches.4
Menstrual Migraine Menstrually related migraine are attacks that occur in at least 3 consecutive cycles on day 1 ⫾ 2 of menstruation in at least 2 of 3 menstrual cycles, and additionally at other times of the cycle (Table). When evaluating adolescent girls and adult women with migraine, it is important to obtain a menstrual history. It is helpful to keep in mind that in adolescent girls in the first year or 2 after menarche, menstrual periods may be irregular. Also, certain types of hormonal contraceptives such as medroxyprogesterone (Depo-ProveraR) or etonogesterol (NexplanonR) implant may be associated with irregular menses. Exacerbation in severity and frequency of headaches related to menses may be helpful information in migraine management. In some women there is no relationship of their headaches to menses. However, approximately 60% of women with migraine experience menstrually related migraine. Pure menstrual migraine occurs in approximately 10%-14%.5 Menstrually related migraine is probably due to decrease in estrogen and increase in prostaglandin levels.6 Treatment can be problematic, making it very important to keep an accurate headache diary. Menstrually related migraine headaches are generally more severe, longer in duration, and generally have a poorer response to analgesics than nonmenstrual attacks in women.7 For miniprophylaxis of these menstrually related headaches, a short course of nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen sodium (550 mg twice
1071-9091/16/$-see front matter & 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.spen.2016.01.005
Migraine and hormones
93
Table Menstrually Related Migraine without Aura-ICHD-3 Beta Version Diagnostic Criteria (A) Attacks, in a menstruating woman, fulfilling criteria for migraine without aura and criterion B below. (B) Documented and prospectively recorded evidence over at least 3 consecutive cycles has confirmed that attacks occur on day 1 ⫾ 2 (ie, days 2 to þ3) of menstruation in at least 2 of 3 menstrual cycles, and additionally at other times of the cycle. ICHD, International Classification of Headache Disorders.
a day) or diclofenac (50 mg 3 times a day) for 2-4 days before menses and continuing through day 3 of the menstrual period may be helpful. Triptans such as sumatriptan (25 mg 3 times a day), frovatriptan (2.5 mg twice daily), or zolmitriptan (2.5 mg 3 times daily) may also be a reasonable dosing regimen for menstrual migraine beginning on day 2 of the menstrual cycle and continuing for several days.8 Oral magnesium such as magnesium oxide (500 mg twice a day) is also safe and may be used similarly to NSAIDs.9 For adolescent girls and young women on standard migraine prophylaxis such as antiepileptic drugs, beta blockers, calcium channel blockers, and antidepressants, doses may be transiently increased 5-7 days before the onset of menses and continue through the end of the cycle. However, these miniprophylaxis regimens depend on some degree of regularity in the menstrual cycle, which in younger adolescent girls are generally not the case.
Combination Oral Contraceptives and Migraine COCs are frequently prescribed for adolescent girls for a variety of medical issues besides contraception such as menorrhagia and treatment of acne. These newer oral contraceptives use a combination of progestin and lowdose ethinyl estradiol (o50 μg). Many of the medications used in prophylaxis may generally increase the metabolism of COCs, negatively affecting their availability. COCs may improve or worsen migraine or have no effect on the frequency or severity of attacks. Typically, migraine in patients susceptible to hormonal changes would worsen during the placebo week with decreasing levels of estrogen. In some patients, omitting the placebo-free week with sequential COCs in an extended cycle for 12 weeks may improve headaches. Changing to alternate forms of contraception may be necessary, such as progestin only oral contraceptives, Depo-proveraR injections, NexplanonR implant, or intrauterine device in some refractory patients. With higher systemic levels of estrogens, the COCs may induce aura with migraine headaches in patients who previously have not had a history of it. Furthermore, migraines may occur for the first time in women taking COCs. Other higher estrogenic states such as pregnancy may induce similar changes. Migraine is known to be an independent risk factor for ischemic stroke, and this is especially true for migraine with aura. In women 25-30 years of age, with migraine with aura—their risk of ischemic stroke after taking COCs approaches 18 of 100,000 per year compared with 3 of 100,000 per year in women with
migraine without aura.10 This information validates current World Health Organization contraindication in using COCs in women with migraine with aura.11 In women with migraine without aura, risks of ischemic stroke should be considered with other risk factors such as cigarette smoking, hypertension, or other thromboembolic medical conditions.
Pregnancy and Migraine Pregnancy in adolescents is almost always unplanned, so discussions of effects of pregnancy on migraine are an important consideration in older adolescent girls. This topic should also be discussed with patients in the course of routine follow-up of their migraine headaches. Migraine can be significantly affected by the hormonal changes associated with pregnancy; a transient worsening may occur during the first trimester or it may improve during pregnancy, particularly in women with migraine without aura. In patients with migraine with aura, hormonal effects related to pregnancy may increase attacks. In some susceptible women, migraine may occur for the first time during pregnancy. In addition to the hormonal changes, stress, disrupted sleep, nausea, and dehydration may all worsen migraine. Aura with migraine headaches may make its first appearance in women during pregnancy without a prior history of it with their headaches. Recent studies suggest that severe maternal migraines may increase the occurrence of pre-eclampsia and severe nausea and vomiting, but these symptoms are not associated with unfavorable pregnancy outcomes.12 However, a recent population-based study in Taiwan by Chen et al13 concluded that women with migraines were at increased risk of having low birth weight and preterm babies, pre-eclampsia, and delivery by Cesarean section. Migraine may also worsen during the postpartum period related to rapid decline in estrogen levels and effects of sleep deprivation. Adhering to good lifestyle practices is the first line of management in women during pregnancy to minimize headaches. These include adequate hydration, good sleep hygiene, and regular meals. Nonpharmacologic therapies may be particularly beneficial, such as biofeedback or relaxation therapy. Triptans, ergots, and aspirin are not to be used during pregnancy. NSAIDs such as ibuprofen, diclofenac, piroxicam, naproxen, and indomethacin are classified by the Food and Drug Administration as category B in the first and second trimesters; however, they are category D in the third
94 trimester. Antiemetics may be helpful as is acetaminophen or hydroxyzine.14 Most prophylactic medications are category C and include amitriptyline, verapamil, or topiramate. Valproate is obviously contraindicated during pregnancy because of its high incidence of teratogenic effects like neural tube defects. Beta blockers such as propranolol and oral magnesium supplementation generally have the best safety profile for use during pregnancy.
References 1. Bigal ME, Liberman JN, Lipton RB: Age-dependent prevalence and clinical features of migraine. Neurology 246-251, 2006 2. Zacur HA: Hormonal changes throughout life in women. Headache 46: S49-S54, 2006 (suppl 2) 3. Martin VT, Behbehani M: Ovarian hormones and migraine headache: Understanding mechanisms and pathogenesis—Part I. Headache 46:3-23, 2006 4. Chai NC, Peterlin BL, Calhoun AH: Migraine and estrogen. Curr Opin Neurol 27:315-324, 2014
A. Pakalnis 5. Headache Classification Committee of the International Headache Society (IHS): The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33:629-808, 2013 6. Crawford MJ, Lehman L, Slater S, et al: Menstrual migraine in adolescents. Headache 49:341-347, 2009 7. Pringsheim T, Davenport WJ, Dodick D: Acute treatment and prevention of menstrually related migraine headache: Evidence-based review. Neurology 70:1555-1563, 2008 8. Lay CL, Broner SW: Migraine in women. Neurol Clin 27:503-511, 2009 9. Silberstein SD, Hutchinson SL: Diagnosis and treatment of the menstrual migraine patient. Headache 48:S115-S123, 2008 (suppl 2) 10. Allais G, Gabellari IC, De Lorenzo C, et al: Oral contraceptives in migraine. Expert Rev Neurother 9:381-393, 2009 11. Allais G, Gabellari IC, Mana O, et al: Migraine and stroke: The role of oral contraceptives. Neurol Sci 29:S12-S14, 2008 (suppl 2) 12. Bánhidy F, Acs N, Horváth-Puhó E, Czeizel AE: Pregnancy complications and delivery outcomes in pregnant women with severe migraine. Eur J Obstet Gynecol Reprod Biol 134:157-163, 2007 13. Chen HM, Chen SF, Chen YH, Lin HC: Increased risk of adverse pregnancy outcomes or women with migraines: A nationwide population-based study. Cephalalgia 30:433-438, 2010 14. Digre KB: Headaches during pregnancy. Clin Obstet Gynecol 56:317-329, 2013
Introduction Ovarian hormones play a significant role in some adolescent girls and young adult women with migraine. Migraine is 3 times more common in adult women than men, and in the adolescent population, migraine is more frequent in girls than boys.1 Migraine headaches among adolescent girls usually tend to begin around the time of menarche.2 During the female reproductive cycle, hormonal changes can influence migraine. The sex hormone axis involves interplay between the hypothalamus, pituitary, and ovaries. Gonadotropin releasing hormone is synthesized in the hypothalamus and binds to receptors in the anterior pituitary gland, which in turn is stimulated to release follicle stimulating hormone (FSH) and luteinizing hormone (LH). Early in the regular 28-day menstrual cycle, FSH and LH induce development of an ovarian follicle that produces estrogen and progesterone. A certain critical increase in estrogen levels leads to a surge in LH levels, which induces ovulation at midcycle. If fertilization does not occur, the luteal phase persists with initially high levels of estrogen and progesterone produced by the ovarian follicle. At the end of the luteal phase, progesterone withdrawal induces menses.3 Fluctuations in estrogen levels influence migraine attacks, with estrogen withdrawal before menses probably being a notable trigger. In adolescent girls and adult women taking combination oral contraceptives (COCs), headaches tend to increase during the placebo week with decreased estrogen From the Departments of Pediatrics and Neurology, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH. Address reprint requests to Ann Pakalnis, MD, Departments of Pediatrics and Neurology, Nationwide Children’s Hospital, The Ohio State University, 700 Children’s Dr, Columbus, OH 43205. E-mail: Ann.pakalnis@ nationwidechildrens.org
92
levels present. Estrogen withdrawal also takes place during the postpartum period that is a very vulnerable time for hormonally related migraine headaches.4
Menstrual Migraine Menstrually related migraine are attacks that occur in at least 3 consecutive cycles on day 1 ⫾ 2 of menstruation in at least 2 of 3 menstrual cycles, and additionally at other times of the cycle (Table). When evaluating adolescent girls and adult women with migraine, it is important to obtain a menstrual history. It is helpful to keep in mind that in adolescent girls in the first year or 2 after menarche, menstrual periods may be irregular. Also, certain types of hormonal contraceptives such as medroxyprogesterone (Depo-ProveraR) or etonogesterol (NexplanonR) implant may be associated with irregular menses. Exacerbation in severity and frequency of headaches related to menses may be helpful information in migraine management. In some women there is no relationship of their headaches to menses. However, approximately 60% of women with migraine experience menstrually related migraine. Pure menstrual migraine occurs in approximately 10%-14%.5 Menstrually related migraine is probably due to decrease in estrogen and increase in prostaglandin levels.6 Treatment can be problematic, making it very important to keep an accurate headache diary. Menstrually related migraine headaches are generally more severe, longer in duration, and generally have a poorer response to analgesics than nonmenstrual attacks in women.7 For miniprophylaxis of these menstrually related headaches, a short course of nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen sodium (550 mg twice
1071-9091/16/$-see front matter & 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.spen.2016.01.005
Migraine and hormones
93
Table Menstrually Related Migraine without Aura-ICHD-3 Beta Version Diagnostic Criteria (A) Attacks, in a menstruating woman, fulfilling criteria for migraine without aura and criterion B below. (B) Documented and prospectively recorded evidence over at least 3 consecutive cycles has confirmed that attacks occur on day 1 ⫾ 2 (ie, days 2 to þ3) of menstruation in at least 2 of 3 menstrual cycles, and additionally at other times of the cycle. ICHD, International Classification of Headache Disorders.
a day) or diclofenac (50 mg 3 times a day) for 2-4 days before menses and continuing through day 3 of the menstrual period may be helpful. Triptans such as sumatriptan (25 mg 3 times a day), frovatriptan (2.5 mg twice daily), or zolmitriptan (2.5 mg 3 times daily) may also be a reasonable dosing regimen for menstrual migraine beginning on day 2 of the menstrual cycle and continuing for several days.8 Oral magnesium such as magnesium oxide (500 mg twice a day) is also safe and may be used similarly to NSAIDs.9 For adolescent girls and young women on standard migraine prophylaxis such as antiepileptic drugs, beta blockers, calcium channel blockers, and antidepressants, doses may be transiently increased 5-7 days before the onset of menses and continue through the end of the cycle. However, these miniprophylaxis regimens depend on some degree of regularity in the menstrual cycle, which in younger adolescent girls are generally not the case.
Combination Oral Contraceptives and Migraine COCs are frequently prescribed for adolescent girls for a variety of medical issues besides contraception such as menorrhagia and treatment of acne. These newer oral contraceptives use a combination of progestin and lowdose ethinyl estradiol (o50 μg). Many of the medications used in prophylaxis may generally increase the metabolism of COCs, negatively affecting their availability. COCs may improve or worsen migraine or have no effect on the frequency or severity of attacks. Typically, migraine in patients susceptible to hormonal changes would worsen during the placebo week with decreasing levels of estrogen. In some patients, omitting the placebo-free week with sequential COCs in an extended cycle for 12 weeks may improve headaches. Changing to alternate forms of contraception may be necessary, such as progestin only oral contraceptives, Depo-proveraR injections, NexplanonR implant, or intrauterine device in some refractory patients. With higher systemic levels of estrogens, the COCs may induce aura with migraine headaches in patients who previously have not had a history of it. Furthermore, migraines may occur for the first time in women taking COCs. Other higher estrogenic states such as pregnancy may induce similar changes. Migraine is known to be an independent risk factor for ischemic stroke, and this is especially true for migraine with aura. In women 25-30 years of age, with migraine with aura—their risk of ischemic stroke after taking COCs approaches 18 of 100,000 per year compared with 3 of 100,000 per year in women with
migraine without aura.10 This information validates current World Health Organization contraindication in using COCs in women with migraine with aura.11 In women with migraine without aura, risks of ischemic stroke should be considered with other risk factors such as cigarette smoking, hypertension, or other thromboembolic medical conditions.
Pregnancy and Migraine Pregnancy in adolescents is almost always unplanned, so discussions of effects of pregnancy on migraine are an important consideration in older adolescent girls. This topic should also be discussed with patients in the course of routine follow-up of their migraine headaches. Migraine can be significantly affected by the hormonal changes associated with pregnancy; a transient worsening may occur during the first trimester or it may improve during pregnancy, particularly in women with migraine without aura. In patients with migraine with aura, hormonal effects related to pregnancy may increase attacks. In some susceptible women, migraine may occur for the first time during pregnancy. In addition to the hormonal changes, stress, disrupted sleep, nausea, and dehydration may all worsen migraine. Aura with migraine headaches may make its first appearance in women during pregnancy without a prior history of it with their headaches. Recent studies suggest that severe maternal migraines may increase the occurrence of pre-eclampsia and severe nausea and vomiting, but these symptoms are not associated with unfavorable pregnancy outcomes.12 However, a recent population-based study in Taiwan by Chen et al13 concluded that women with migraines were at increased risk of having low birth weight and preterm babies, pre-eclampsia, and delivery by Cesarean section. Migraine may also worsen during the postpartum period related to rapid decline in estrogen levels and effects of sleep deprivation. Adhering to good lifestyle practices is the first line of management in women during pregnancy to minimize headaches. These include adequate hydration, good sleep hygiene, and regular meals. Nonpharmacologic therapies may be particularly beneficial, such as biofeedback or relaxation therapy. Triptans, ergots, and aspirin are not to be used during pregnancy. NSAIDs such as ibuprofen, diclofenac, piroxicam, naproxen, and indomethacin are classified by the Food and Drug Administration as category B in the first and second trimesters; however, they are category D in the third
94 trimester. Antiemetics may be helpful as is acetaminophen or hydroxyzine.14 Most prophylactic medications are category C and include amitriptyline, verapamil, or topiramate. Valproate is obviously contraindicated during pregnancy because of its high incidence of teratogenic effects like neural tube defects. Beta blockers such as propranolol and oral magnesium supplementation generally have the best safety profile for use during pregnancy.
References 1. Bigal ME, Liberman JN, Lipton RB: Age-dependent prevalence and clinical features of migraine. Neurology 246-251, 2006 2. Zacur HA: Hormonal changes throughout life in women. Headache 46: S49-S54, 2006 (suppl 2) 3. Martin VT, Behbehani M: Ovarian hormones and migraine headache: Understanding mechanisms and pathogenesis—Part I. Headache 46:3-23, 2006 4. Chai NC, Peterlin BL, Calhoun AH: Migraine and estrogen. Curr Opin Neurol 27:315-324, 2014
A. Pakalnis 5. Headache Classification Committee of the International Headache Society (IHS): The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33:629-808, 2013 6. Crawford MJ, Lehman L, Slater S, et al: Menstrual migraine in adolescents. Headache 49:341-347, 2009 7. Pringsheim T, Davenport WJ, Dodick D: Acute treatment and prevention of menstrually related migraine headache: Evidence-based review. Neurology 70:1555-1563, 2008 8. Lay CL, Broner SW: Migraine in women. Neurol Clin 27:503-511, 2009 9. Silberstein SD, Hutchinson SL: Diagnosis and treatment of the menstrual migraine patient. Headache 48:S115-S123, 2008 (suppl 2) 10. Allais G, Gabellari IC, De Lorenzo C, et al: Oral contraceptives in migraine. Expert Rev Neurother 9:381-393, 2009 11. Allais G, Gabellari IC, Mana O, et al: Migraine and stroke: The role of oral contraceptives. Neurol Sci 29:S12-S14, 2008 (suppl 2) 12. Bánhidy F, Acs N, Horváth-Puhó E, Czeizel AE: Pregnancy complications and delivery outcomes in pregnant women with severe migraine. Eur J Obstet Gynecol Reprod Biol 134:157-163, 2007 13. Chen HM, Chen SF, Chen YH, Lin HC: Increased risk of adverse pregnancy outcomes or women with migraines: A nationwide population-based study. Cephalalgia 30:433-438, 2010 14. Digre KB: Headaches during pregnancy. Clin Obstet Gynecol 56:317-329, 2013