Headache ISSN 0017-8748 C 2006 by American Headache Society doi: 10.1111/j.1526-4610.2006.00370.x Published by Blackwell Publishing Review Article Ovarian Hormones and Migraine Headache: Understanding Mechanisms and Pathogenesis—Part 2 Vincent T. Martin, MD; Michael Behbehani, PhD 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 un- der different circumstances depending on their absolute serum levels, constancy of exposure, and types of estro- gen/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. Key words: menstrual migraine, migraine headache, estrogen, progesterone, menstrual cycle, menarche, pregnancy, menopause, lactation Abbreviations: GnRH gonadotropin-releasing hormone, HRT hormone replacement therapy, OCPs oral contra- ceptives, PROGINS progesterone receptor allele, CVA cerebrovascular accident, CNS central nervous system, CI confidence intervals, HR hazard ratio, MAO-B monoamine oxidase-B, NMDA N-methyl-d-aspartate, AUC area-under-the-curve, TNC trigeminal nucleus caudalis, GABA gamma aminobutyric acid (Headache 2006;46:365-386) During part 1 of this series, we reviewed the ge- pathogenesis of migraine headache. Numerous clini- nomic and nongenomic effects of ovarian hormones cal studies also exist to provide clues to how ovarian on the central nervous system as well as the current hormones might modulate migraine headaches. Mi- basic science studies linking them to the pathogene- graine headaches are likely influenced by the different sis of migraine headache. These studies clearly indi- “hormonal milieus” encountered during reproductive cate that ovarian hormones can alter neurotransmit- life events that begin during menarche and continue ter systems theorized to play an important role in the through menopause. The purpose of this manuscript will be to review existing clinical studies examining From the Department of Internal Medicine, University of the course of migraine headache during reproductive Cincinnati College of Medicine Cincinnati, Ohio (Dr. Martin); life events (eg, menarche, menstrual cycles, pregnancy, and Department of Molecular and Cellular Physiology, Uni- lactation, and menopause) as well as after administra- versity of Cincinnati College of Medicine, Cincinnati, Ohio (Dr. Behbehani) tion of exogenous hormones (eg, oral contraceptives [OCPs] and hormone replacement therapy [HRT]). Address all correspondence to Dr. Vincent T. Martin, Depart- ment of Internal Medicine, University of Cincinnati College We will also define the specific serum levels of ovar- of Medicine, 231 Albert Sabin Way, ML 6603, Cincinnati, OH ian hormones encountered during the different repro- 45267-0535, USA. ductive life events and postulate mechanisms through Accepted for publication December 16, 2005. which they might affect migraine headache. 365 366 March 2006 MENARCHE ENDOCRINOLOGY OF THE MENSTRUAL Menarche refers to the onset of menstruation dur- CYCLE ing puberty. The typical age range of menarche is 9.1 The menstrual cycle is divided into follicular and to 17.7 years with a median age of 12.8 years within luteal phases. The follicular phase includes all days American girls.1,2 The initial menstrual cycles are of- from the first day of menstrual bleeding to the day ten anovulatory and may remain so for the first 12 to before ovulation and the luteal phase includes all days 18 months after the onset of menarche. Serum estra- from the first day of ovulation to the last day before diol levels range from 10 to 156 pg/mL during puberty the next menstrual period. The follicular and luteal prior to the onset of ovulatory menstrual cycles; serum phases can further be subdivided into early, mid, and levels of estrogen and progesterone similar to those late time intervals. Serum estradiol levels typically are encountered during the adult menstrual cycle may low during the early to mid-follicular phases (eg, 25 not be reached until several years after the onset of to 50 pg/mL range), peak during the late follicular menarche.3 and early luteal phase (eg, 100 to 400 pg/mL range), The prevalence of migraine is similar in preadoles- plateau during the mid-luteal phase (200 to 300 pg/mL cent boys and girls, but diverges at the time of menar- range), and fall precipitously to levels of 25 to 50 pg/mL che.4 After menarche, the prevalence is 2 to 3 times just prior to menstruation. Serum progesterone lev- higher in girls than in boys and remains so throughout els are extremely low during the follicular phase (<1 most of the reproductive years. The age of onset of ng/mL range), peak during the mid-luteal phase at lev- migraine tends to differ between girls experiencing at- els ranging from 6 to 10 ng/mL, and then fall precipi- tacks of migraine with and without aura. Stewart et al5 tously to levels <2 ng/mL during the late luteal phase reported the peak incidence of migraine was 12 to 13 (Figure 1). years of age for girls experiencing migraine with aura (MWA) (14.1 cases per 1000 person years) and 14 to MENSTRUAL MIGRAINE 17 years of age for those experiencing migraine with- Menstrual migraine has recently been defined out aura (MWoA) (18.9 cases per 1000 person years). by the International Headache Society in the ap- Thus MWoA most commonly begins after the onset of pendix of their diagnostic criteria for headache and menarche, while MWA usually begins shortly before has been divided into 2 subcategories: “menstrually or at the time of menarche. Since ovulation and regular related MWoA” and “pure menstrual MWoA.” The menstrual cycles may not develop for 1 to 2 years after criteria for “menstrually related MWoA” include: menarche, it is likely that the onset of MWoA is asso- ciated with the establishment of the female menstrual cycle. Follicular Luteal Early Mid Late Early Mid Late 500 12 400 10 8 MENSTRUAL CYCLE 300 6 Migraine headaches could theoretically be influ- 200 4 enced by changes in ovarian hormones that occur Level (ng/ml)Level Level (pg/ml) Level 100 Serum Estradiol Estradiol Serum 2 throughout the female menstrual cycle. Knowledge 0 0 Serum Progesterone of the different “hormonal milieus” encountered dur- 1 4 7 10131619222528 ing different phases of the menstrual cycle is essen- Days of Menstrual Cycle tial to an understanding of the effects of ovarian hor- mones on migraine headache. Therefore, in the next Fig 1.—Changes in serum estrogen and progesterone levels dur- several sections, we will review the endocrinology of ing a native menstrual cycle. Day 1 is the first day of menses and the menstrual cycle as well as the potential mecha- day 27 is the last day before the next menstrual period. The fol- licular phase includes all days prior to ovulation and the luteal nisms through which ovarian hormones could modu- phase includes all days after ovulation. The follicular and luteal late menstrual and nonmenstrual migraine headaches. phases can be divided into early, mid, and late time periods. Headache 367 (1) predictable migraine attacks occurring during the difference between the attack characteristics of men- , perimenstrual time period (2 days before to 3 days af- strual and nonmenstrual migraine.14 15 Studies within ter the onset of menstruation), (2) migraines also oc- subspecialty-based clinics, however, suggest that men- cur at other times of the month, and (3) the association strual migraine is more severe, disabling, and as- with menses must be confirmed in 2/3 menstrual cycles. sociated with greater abortive medication use than “Pure menstrual MWoA” is similar to the above crite- nonmenstrually related migraine.16-18 The discrepan- ria, except that migraine headaches are strictly limited cies between specialty- and population-based studies to the perimenstrual time period and do not occur at most likely can be explained by their selection of pa- other times of the menstrual cycle. For the sake of this tients. Subspecialty-based studies may have included a review, we will refer to both types of migraine as “men- greater percentage of “hormonally sensitive” patients strual migraine.” than population-based studies, thus allowing a greater Epidemiology.—The overall prevalence of men- chance of identifying differences between menstrually strual migraine in the general population is approx- related and nonmenstrually related attacks. imately 3%, but it is much higher within populations Effect on MWoA.—Interestingly only attacks of of migraineurs6; 35% to 51% of female migraineurs MWoA occur during the perimenstrual time period. have “menstrually related MWoA,” while 7% to 19% Stewart et al15 reported that attacks of MWoA were have “pure menstrual MWoA”7-13 (Table 1). 2.04 times more likely during the first 2 days of men- Attack Characteristics.—Population-based studies struation, while attacks of MWA occurred with equal of nonselected female migraineurs demonstrate little frequency throughout the menstrual cycle. Johannes Table 1.—Prevalence of Menstrual Migraine in Female Migraineurs∗ Study Method of Ascertainment Prevalence Prevalence Author/Year (n) Population of Menstrual Migraine of PMM of MRM MacGregor/1990