Headache ISSN Hormones, Menstrual Distress, and Migraine Across the Phases of the Menstrual Cycle

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1 Headache ISSN C 2005 by American Headache Society doi: /j x Published by Blackwell Publishing Research Submission Hormones, Menstrual Distress, and Migraine Across the Phases of the Menstrual Cycle Jeffrey L. Kibler, PhD; Jamie L. Rhudy, PhD; Donald B. Penzien, PhD; Jeanetta C. Rains, PhD; G. Rodney Meeks, MD; William Bennett, PhD; Katherine M. Dollar, MA Objective. The primary objectives of the present study were to (1) contrast reproductive hormone levels and ratings of menstrual distress of female migraineurs with those of a control group in each menstrual cycle phase, (2) examine correlations between hormone levels and migraine frequency, severity, and migraine-related disability, and (3) examine correlations between menstrual distress and migraine frequency, severity, and migraine-related disability. A secondary objective was to evaluate the validity of a migraine disability measure modified to reflect 7-day recall. Background. Further controlled, prospective study is needed regarding the temporal relationships between reproductive hormones at each stage of the menstrual cycle and fluctuations in migraine activity across the cycle. Methods. Twenty-three women (17 with migraine, 6 control participants) completed laboratory hormone assays and measures of menstrual distress and disability at each phase of one menstrual cycle, and monitored their headache activity daily during the same cycle. Results. The migraine group evidenced lower premenstrual luteinizing hormone and more menstrual distress symptoms at each phase of the menstrual cycle. Hormones were associated with migraine activity and disability within cycle phases, and across phases in a time-lagged manner. Menstrual distress was associated with ovulatory phase migraine activity and with migraine-related disability across the menstrual cycle. A retrospective 7-day migraine disability measure appeared to be a consistently valid index. Conclusions. Both reproductive hormones and menstrually related distress appear to predict migraine activity and disability. These associations were evident not only for perimenstrual migraine, but also for migraine at each phase of the menstrual cycle. Keywords: hormones, migraine, menstrual cycle, distress, disability Abbreviations: BBT basal body temperature, HDI headache disability inventory, LH luteinizing hormone, MDQ menstrual distress questionnaire, MIDAS migraine disability assessment, d Cohen s effect size (Headache 2005;45: ) From the Center for Psychological Studies, Nova Southeastern University, Ft. Lauderdale, FL (Dr. Kibler); Department of Psychology, University of Tulsa, Tulsa, OK (Dr. Rhudy); Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS (Drs. Penzien); Elliot Hospital, Dartmouth University Medical School, Center for Sleep Evaluation, Manchester, NH (Dr. Rains); Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS (Drs. Meeks and Bennett); and Department of Psychology, Jackson State University, Jackson, MS (Ms. Dollar). Address all correspondence to Dr. Jeffrey L. Kibler, Center for Psychological Studies, Nova Southeastern University, 3301 College Avenue, Ft. Lauderdale, FL Accepted for publication March 10,

2 1182 October 2005 There is growing evidence that migraine headache is related to reproductive hormones for a large percentage of women with migraine, and that these relationships may vary across the phases of the menstrual cycle. 1-3 There is limited evidence that estrogen and progesterone levels are higher in migraine headache patients compared to no-headache controls, and mixed results concerning whether particularly high levels of these hormones during the late luteal and premenstrual phases of the cycle are related to the phenomenon of menstrual migraine. 3-5 However, additional studies are needed that compare hormone levels of migraineurs with a control group, as well as examinations that more clearly establish the specific temporal relationships between the hormones at each stage of the cycle and fluctuations in migraine activity across the cycle. A hypothesis with some empirical support posits that migraine severity during, or in close proximity to menses (ie, within 1 to 2 days) is associated with sharp decreases in the levels of estrogens and progesterone between the luteal phase and menses. 1,2 One study identified a moderate, albeit nonsignificant association between premenstrual migraine severity and greater progesterone levels during the luteal phase. 3 Given the possibility that women with relatively high luteal or premenstrual phase progesterone levels are susceptible to a greater subsequent decrease, this finding is consistent with the contention that migraine is associated with precipitous drops in ovarian hormones. However, replication of the Beckham et al finding is needed because the correlation was based on a small sample of 11 women. Another factor thought to impact migraine headache activity is menstrually related cognitive and physical distress symptoms. 6,7 It is well documented that a substantial subset of women experience variations in emotional distress across the menstrual cycle, with most of these women reporting increased distress at the premenstrual phase, though premenstrual symptoms may or may not meet diagnostic criteria for premenstrual dysphoric disorder. Moreover, data from one small sample suggest linear correlations between migraine activity and various indices of psychological distress are limited to the premenstrual phase. 7 There is some evidence that fluctuations in estrogens and progesterone explain the relationship between menstrually related distress and migraine There has been an increase in focus recently on disability as an index of the functional impact of migraines. While there is evidence that migraine-related disability may vary by menstrual cycle phase, 12 it is not yet clear whether migraine disability is associated with levels of reproductive hormones. Phase-related negative affect in response to psychological distress may also be associated with migraine disability. 6 The most widely used assessment of migraine-related disability, the migraine disability assessment (MIDAS) questionnaire, entails a retrospective global self-report over a relatively long time period (ie, 3 months). 13 Self-report ratings over a 3-month period may be limited by recall ability, and would not be adequately sensitive to phasic changes in migraine severity as occur within a single menstrual cycle. Thus, for the purposes of assessing disability within each menstrual cycle phase in the present study, an author-constructed, modified MIDAS questionnaire with 7-day retrospective report was adapted. The objectives of the present study were to (1) examine in each phase of the menstrual cycle, hormone levels and ratings of menstrual distress for women with migraine compared with a headache-free control group, (2) examine relationships of hormone levels and menstrual distress with migraine frequency, severity, and disability in the migraine group, and (3) examine the validity of a modified 7-day timeline for the MIDAS. METHOD Participants. A total of 39 participants were recruited for the present study from community advertisements, university distribution, and newspaper announcements. Of 39 intake interviews, 28 participants met criteria for a migraine headache disorder and 9 met criteria for the control group. Exclusion criteria for all candidates were: irregular menses (not cycling every 25 to 32 days), use of oral contraceptives or hormone preparations in the past 6 months, medical problems that might affect headache and/or circulating hormones, reached menopause, taking

3 Headache 1183 medications that could influence the menstrual cycle or reproductive hormones, current pregnancy or trying to get pregnant, or gave birth or breastfed child in the past 6 months. All the participants agreed to use nonhormonal means of contraception as needed while participating in the study. A candidate for the migraine group was invited to complete the study if she reported experiencing at least three migraines per month beginning more than 6 months prior, and met International Headache Society (IHS) diagnostic criteria for migraine headache at intake. The IHS diagnosis was determined by the second author or clinical psychology interns using the structured diagnostic interview for headache 14 and verified by the computer scoring program. 15,16 Participant records were reviewed by a neurologist to rule out medical problems that would contraindicate participation. A candidate for the control group was included only if she reported seldom or never experiencing headache, and that any headache experienced was mild and nonproblematic. Because some candidates who were interviewed did not meet all study inclusion criteria, missed multiple follow-up sessions, or were missing headache diary data, the analyses included a sample of 23 women (17 meeting migraine criteria and 6 controls). Three participants in the migraine group missed one of their four follow-up sessions one at each of the menses, luteal, and premenstrual phases. Therefore, hormone data were only available for 16 of 17 migraine participants at these phases. To avoid overlooking hormone differences between controls and participants actually experiencing migraine during the study, another four participants were excluded from the migraine group for comparisons with the control group because they did not experience a significant migraine during the study. These four participants were not excluded from the correlational analyses, as they are viewed as representing the less severe end of the continuum of migraine during the study period. Using procedures described in a previous study, 3 examination of migraine intensity ratings indicated that the migraine group consisted of 2 participants with menstrual migraine, 4 with menstrually related migraine, and 11 with menstrually unrelated migraine. Mean age of participants was 35 (range = 23 to 46) and the two groups did not differ significantly in age. All participants were gainfully employed and the groups did not differ in family income distribution. Eleven of the 17 women in the migraine group were Caucasian/non-Hispanic, 4 were African American, 1 was Hispanic, and 1 was of Asian decent. The 6 control participants all identified themselves as Caucasian/ non-hispanic. The present study was reviewed and approved by the appropriate University Institutional Review Board. Participants were paid $80 for completion of the study. All participants signed an informed consent after the study procedures were fully explained. Hormone Assays. Participants reported for phlebotomist drawn blood samples used to derive hormone assays at four points during a single menstrual cycle: menses (between days 1 and 3 of bleeding), ovulation [within 24 hours of basal body temperature (BBT) rising 0.4 Fto0.6 F], luteal phase (5 to 7 days prior to onset of next menses), and premenstrual phase (1 to 3 days prior to onset of next menses). Onset of next menses was estimated by retrospective self-report of the length of the previous two menstrual cycles and the length between menses and ovulation. The blood samples were frozen for later analysis of hormone levels. Steroid Hormone Assays. Assays for the steroid hormones progesterone and estradiol were performed utilizing an ACS:180 Immunoassay Analyzer (Bayer Corporation, Dallas, TX) according to the manufacturer s instructions. Sensitivity for the progesterone assay was 0.24 ng/ml and the assay displayed a range of detection from 1 to 60 ng/ml. Inter- and intra-assay coefficients of variability for the progesterone assay were 10.2% and 4.3%, respectively. The estradiol assay displayed a sensitivity of 5.4 pg/ml and a range from 10 pg to 1000 pg/ml. Coefficients of variability for the estradiol assay were 9.3% between assays and 5.1% within assays. Protein Hormone Assays. Assays for luteinizing hormone (LH) and prolactin were also performed using the ACS:180 Immunoassay Analyzer. Sensitivity for the LH assay was 0.03 miu/ml and the effective range of the assay was between 1 and 200 miu/ml. Inter- and intra-assay coefficients of variability for the LH assay were 7.0% and 3.3%, respectively.

4 1184 October 2005 The PRL assay expressed a sensitivity of 0.1 ng/ml and a range of detection from 1 to 200 ng/ml. Interand intra-assay coefficients of variability for the prolactin assay averaged 6.8% and 2.8%, respectively. Basal Body Temperature Recording. Participants were given a basal thermometer and daily temperature chart and instructed to begin recording their BBT approximately 3 days prior to menses onset and continue for 35 days. Participants were asked to take their temperature using the thermometer provided every morning before getting out of bed or engaging in physical activity. Participants were instructed to keep the thermometer in their mouth for a minimum of 5 minutes and then immediately record the temperature in the chart to the nearest tenth of a degree (F). When a 0.4 Fto0.6 F increase in BBT was observed, participants were instructed to return to the laboratory for the ovulation visit. Headache Ratings. Participants were asked to rate their headache intensity on an 11-point Likert-type scale four times per day (meal times and at night before sleeping were suggested as anchors) for 35 days. The intensity ranged from 0 (none) to 10 (extremely painful). The ratings were made on a grid indicating the time of ratings. Intake Session Self-Report Measures. A battery of self-report measures including information about medical history, headache history, and psychological/emotional functioning was collected as part of the preliminary intake. Completion of the intake battery required approximately 60 minutes. Several intake self-report measures were included for purposes beyond the scope of the present article. Thus, only the measures relevant to our present focus are described below. Menstrual Distress Questionnaire. The menstrual distress questionnaire (MDQ) is a widely used self-report instrument designed to measure symptoms associated with the menstrual cycle. Participants are asked to rate the presence of symptoms on a 4-point Likert-type scale ranging from 1 (not at all) to 4 (to a high degree). The MDQ contains eight subscales (pain, concentration, arousal, autonomic reactions, negative affect, behavioral change, water retention, and control) that load on two higher order factors (somatic and psychological/behavioral). 17,18 The MDQ has been shown to be a reliable and valid measure of menstrual symptomatology. 17,19 Migraine Disability Assessment. The migraine disability assessment (MIDAS) is a 5-item questionnaire used to quantify migraine-related disability in terms of missed days of paid work or school, housework, and nonwork family/leisure activities. 13,20 The participant is asked to retrospectively evaluate the level of migraine disability over the previous 3 months. Each question is used to assess either days of missed activity or days in which productivity was reduced more than half. In scoring the items, a day with productivity reduced by more than half is considered a missed day. The total MIDAS score is a sum of missed days of work, missed days of housework, and missed days of nonwork activities due to migraine (ie, if a headache impacted all three domains on the same day, this result in 3 missed days in the total score). Psychometric examination of the MIDAS has revealed adequate internal consistency, good concurrent validity (r = 0.63 to 0.69), and high test retest reliability (r = 0.80). 13,20 Headache Disability Inventory. The headache disability inventory (HDI) is composed of 25 items that contribute to either the emotional function subscale or role function subscale. 21 There are three response options for each item: Yes, Sometimes, or No. The HDI is a single point-in-time assessment of headache disability (ie, how respondent feels at time of assessment rather than retrospective report). Follow-Up Session Self-Report Measures. Self-report measures pertaining to psychological/emotional functioning were also collected at each blood draw visit (follow-up session). Completion of the follow-up battery required approximately 45 minutes. Several follow-up self-report measures were included for purposes beyond the scope of the present article. Thus, only the measures relevant to our present focus are described here. The MDQ was readministered at each follow-up visit. Modified MIDAS. A modified MIDAS questionnaire with 7-day retrospective report was adapted for the present study by simply changing the wording in the MIDAS instructions from 3 months to 7 days. This modification was made to estimate migraine disability in the week prior to, and including the blood draw for each menstrual cycle phase.

5 Headache 1185 Procedure. Each participant was assessed at baseline and at one visit during each of the menses, ovulation, luteal, and premenstrual phases of one menstrual cycle. At baseline, participants were given an overview of the study, assessed using the structured interview for headache, and filled out the self-report questionnaire battery. After filling out questionnaires, participants used a calendar to retrospectively track the timing of their last two menstrual cycles. This account was used to estimate the onset of the next two menses. Participants were then trained how to use the daily headache diary, record BBT, and identify their menstrual cycle phases. Participants were asked to return to the clinic for follow-up visits upon first sign of spotting/bleeding (menses), when BBT increased 0.4 Fto0.6 F (ovulation), within 5 to 7 days prior to the next menses (luteal phase), and within 1 to 3 days prior to the next menses (premenstrual phase). To both enhance and ascertain the accuracy of timing for follow-up visits, the project coordinator (2nd author) maintained daily contact with participants regarding menses and temperature changes beginning 2 days prior to the anticipated time of each follow-up visit. In the event that the follow-up visit/blood draw could not be coordinated to reflect the target days (eg, in two cases menses began before the premenstrual visit), the data were not included in the analysis. Participants were asked to avoid making substantial lifestyle or dietary changes and to strive to maintain typical activity/exercise level and sleep patterns throughout the duration of the study. At each followup visit, blood was drawn by the University laboratory, a self-report questionnaire battery was administered to assess information about migraine disability (and measures of stress and emotional functioning that are not a focus of the present article). After participants completed all four follow-up visits, the daily diaries and BBT records were collected, and participants were reimbursed for their participation. Data Reduction and Analyses. The daily headache ratings were used to calculate a migraine intensity index score by averaging the migraine intensity ratings made during the 3 days that best characterize each menstrual cycle phase (days 1 to 3 of menses, 3 days surrounding rise in BBT, 5 to 7 days, and 1 to 3 days prior to the next menses). Migraine frequency was estimated by summing the number of days out of three with a migraine in each phase. Square root transformations were conducted for the hormone measures and for the migraine intensity and frequency scores to approximate normal distributions. The results presented below reflect the transformed values. t-tests were utilized to assess between-groups differences for each of the hormone measures at each menstrual cycle phase. Pearson product moment correlations were utilized to assess associations of progesterone, estradiol, prolactin, and menstrual distress with migraine activity and disability, the covariation of progesterone, estradiol, prolactin with menstrual distress, and the associations of the original and modified MIDAS scales with a third measure of disability (HDI). RESULTS Comparison With Control Group. Results of between-group comparisons for the hormone measures indicated only a trend toward significance for lower premenstrual LH in the migraine group compared with the control group [t = 2.12, P =.051, d (Cohen s effect size) = 1.01)]. Between-group comparisons also revealed that the migraine group tended to report greater menstrual distress at each phase (see Table). However, due to the high degree of variability in MDQ scores in the migraine group, this difference was only significant in the menses phase (t = 2.36, P <.05, d = 1.01) [the MDQ differences approached significance for the ovulatory phase (t = 1.82, P =.081, d = 0.78) and luteal phase (t = 1.78, P =.089, d = 0.76)]. Correlations in Migraine Group. Hormones and Migraine Frequency. Migraine frequency at the ovulatory phase was significantly associated with menses phase prolactin (r = 0.55, P <.05). Migraine frequency during the luteal phase was inversely related to luteal progesterone (r = 0.56, P <.05). Migraine frequency during the premenstrual phase was inversely associated with prolactin at the premenstrual (r = 0.65, P <.01), luteal (r = 0.50, P <.05), and menses phases (r = 0.55, P <.05). Hormones and Migraine Intensity. Migraine intensity ratings during menses were significantly associated with menses progesterone (r = 0.54, P <.05).

6 1186 October 2005 Table. Comparison of Mean and Standard Deviation Menstrual Distress Questionnaire Scores Between Headache Groups Menstrual Cycle Phase Menses Ovulatory Luteal Premenstrual Headache group M SD M SD M SD M SD Migraine Control P <.05. P <.10. A significant association was observed between luteal phase migraine intensity and luteal progesterone (r = 0.60, P <.05). Premenstrual migraine intensity was related to premenstrual prolactin (r = 0.52, P <.05). Hormones and Migraine Disability (Modified MIDAS). Luteal phase migraine disability was inversely related to luteal progesterone ( 0.70, P <.01). Premenstrual phase migraine disability was inversely related to luteal progesterone ( 0.70, P <.01) and luteal estradiol ( 0.60, P <.05), and positively related to menses estradiol (0.78, P <.001). Menstrually Related Distress and Migraine Frequency. Ovulatory phase migraine frequency was positively related to ovulatory MDQ scores (r = 0.56, P <.05). The relationship of ovulatory migraine frequency to menses MDQ scores approached significance (r = 0.46, P =.074). Menstrually Related Distress and Migraine Intensity. Ovulatory phase migraine intensity was positively related to ovulatory MDQ scores (r = 0.64, P <.01). The ovulatory migraine intensity-menses MDQ association approached significance (r = 0.49, P =.053). Menstrually Related Distress and Migraine Disability (Modified MIDAS). Menses phase migraine disability was positively related to menses MDQ scores (0.49, P <.05). Ovulatory phase disability was related to ovulatory phase MDQ scores (0.58, P <.05), menses MDQ scores (0.60, P <.01), and luteal MDQ scores (0.50, P <.05). A trend toward significance was observed for the relationship of luteal phase disability to luteal MDQ scores (0.46, P =.073). Premenstrual phase disability was related to luteal MDQ scores (0.52, P <.05), and the relationship of premenstrual phase disability to premenstrual MDQ scores approached significance (0.45, P =.070). Covariation Among Hormones and Menstrually Related Distress. Menses MDQ scores were inversely related to ovulatory phase progesterone (r = 0.52, P <.05). The relationship of menses MDQ scores to menses phase prolactin approached significance (r = 0.48, P =.069). Luteal MDQ scores were inversely associated with menses progesterone (r = 0.74, P <.01) and the relationship between luteal MDQ and premenstrual progesterone approached significance (r = 0.50, P =.068). A trend toward significance was also observed for the relationship of premenstrual MDQ to menses progesterone (r = 0.45, P =.089). Evaluation of Modified MIDAS. A small correlation was observed between the original MIDAS (with 3-month recall) and the HDI, both measured at intake (r = 0.30). In comparison, small to moderate correlations (r = 0.32 to 0.48) were observed between the revised MIDAS with 7-day recall and the HDI, which were both measured at each phase of the menstrual cycle. COMMENTS The results of the present study generally indicate a lack of differences in hormone levels between women with migraine headache and controls. The only between-group difference was in premenstrual LH level. The migraine group did, however, report greater levels of menstrually related distress at each phase of

7 Headache 1187 the menstrual cycle. Within the migraine group, reproductive hormones and menstrually related distress were associated with migraine activity and migraine disability assessed at the same phase and across phases. The finding of lower premenstrual LH must be interpreted with caution. Given the small sample sizes, replication is needed before generalizable conclusions can be drawn from this effect. Our null findings concerning group differences in the other hormone variables are in contrast with some prior reports. 4,5 Although the between-groups effect sizes for hormone comparisons would not have been significant with much larger samples, the low sample sizes also limit the generalizability of these findings. One potential explanation for our null findings is that our migraine group was not preselected on the basis of an identified menstrual migraine association. Although it might be expected that any group differences in hormones between migraineurs and controls would be accentuated among a pure menstrual migraine sample, results have been mixed. 4,5 In contrast to the examination of group differences, our correlational findings within the migraine group concerning relationships of hormone levels with migraine activity and migraine disability were compelling. In addition to the relationships of luteal phase migraine frequency with luteal phase progesterone, and premenstrual phase migraine frequency with premenstrual phase prolactin, ovulatory and premenstrual phase migraine frequency were associated with lower prolactin at previous cycle phases, supporting the hypothesis of time-lagged effects of hormones on migraine activity. 1,2 These findings concerning prolactin are notable, as previous studies have generally been inconclusive, revealing nonsignificant trends for both higher prolactin 5 and lower prolactin 4 in migraine patients compared with controls. Migraine intensity ratings at menses were associated with lower progesterone. Consistent with the findings for migraine frequency, luteal phase migraine intensity was associated with luteal progesterone and premenstrual phase migraine intensity was associated with premenstrual prolactin. Unlike the time-lagged results for migraine frequency, neither progesterone nor prolactin correlated with migraine intensity across cycle phases. Taken together, these associations contrast with studies that have suggested higher progesterone levels are associated with migraine activity 3-5, and also do not substantiate prior evidence suggesting time-lagged effects of hormone levels on migraine severity. 1-3 The conflicting evidence among the handful of available studies warrants additional study to clarify the relationship of progesterone levels to migraine headache, as well as the temporal relationships of hormone levels with migraine severity. Overall our findings relating hormones to migraine frequency and severity suggest protective effects of prolactin and progesterone. In addition to predicting migraine activity, luteal progesterone levels predicted migraine-related disability. Higher disability ratings at both the luteal and premenstrual phases were associated with low luteal progesterone. Premenstrual disability was also inversely related to luteal estradiol, but was positively correlated with menses estradiol, suggesting the possibility that changes in the relative levels of estradiol within the menstrual cycle are associated with migraine-related disability. With regard to relationships of menstrual distress to migraine, there were positive relationships of both ovulatory and menses phase MDQ scores with ovulatory phase migraine frequency and intensity. In contrast, MDQ symptoms were related to migraine disability at each phase of the menstrual cycle a finding consistent with Woods hypothesis concerning negative affect and disability. 6 Taken together with the observation that menstrually related symptoms indexed by the MDQ were highest in the menses phase (see Table), it appears that these symptoms are important in the development of migraine. However, our data suggest the effects of perimenstrual distress symptoms may be manifested in migraine at the ovulatory phase. It was surprising that menstrually related distress in the premenstrual and menses phases were not significantly associated with perimenstrual migraine measures. This result contrasts with the findings of Holm et al. 7 One possible explanation for our lack of association between premenstrual MDQ and migraine is that other predictors of perimenstrual migraine moderated or suppressed the effects of menstrual distress. A more in-depth multivariate approach would be needed to address this hypothesis.

8 1188 October 2005 Although our results concerning the covariation of hormones and menstrual distress provided some limited support for the hypothesis that greater progesterone may be protective against menstrually related distress, 22 this was not true for premenstrual phase distress symptoms in the present study. It is interesting that there was even greater evidence in the present study to support another model with the exception of ovulatory menstrual distress, MDQ score predicted progesterone at the following phase. One potential explanation for these effects is that distress impacts the activity of the central nervous system neurotransmitters, which in turn affect subsequent hormone secretion. Our results concerning the validity of a revised MIDAS with 7-day recall suggest this scale correlates with the HDI at least as well as the original MIDAS. Although a stronger conclusion could be made if both versions of the MIDAS were administered at the same time point and correlations of both with the HDI were assessed, these preliminary findings concerning the revised MIDAS are encouraging. The conclusions from our study are limited by the reliance on a single serum value within a 3-day window to index hormone activity for a menstrual cycle phase. Although we enhanced the validity of this method by utilizing temperature patterns and participant report of average cycle length, it is possible that there could have been error in estimating the exact ovulatory, luteal, and premenstrual phase-timing and that the single serum value was not representative of a participant s hormone levels during that phase. This issue likely posed the greatest threat to estimating ovulatory hormone levels. A single hormone measurement obtained during the ovulatory interval may not accurately depict the hormone levels of that interval because the serum levels change rapidly during that phase and temperature changes may not always identify the time of ovulation. The headache ratings in the present study were not specifically limited to migraine. Participants were not trained to discern migraine from tension or other types of headache. Therefore, our findings are limited by the possibility that participants in the migraine group experienced headache other than migraine. Another limitation is our use of a single menstrual cycle. Among the difficulties this presents the inability to truly project time-lagged relationships from the end of a cycle into the beginning of the next cycle. Despite the limitations of our study, the correlational findings provide further substantial support for associations of menstrually related hormone levels and distress with migraine frequency, intensity, and disability. Acknowledgments: Research conducted at the University of Mississippi Medical Center, Head Pain Center (Department of Psychiatry and Human Behavior), and Department of Obstetrics and Gynecology. Portions of this article were presented at the 2003 and 2004 meetings of the American Headache Society and the 2004 meeting of the Society of Behavioral Medicine. The authors gratefully acknowledge Marilyn Bray, manager of the University of Mississippi Medical Center, Pavilion Clinical Laboratory for oversight of phlebotomy procedures, Nancy Brewer for conducting initial telephone screens with potential study participants, Lara Dhingra and Kim Laubmeir for assistance with data collection, and Mindy Ma for comments on a previous version of this article. Financial Support: Funded by an American Headache Society/Pfizer Headache Research Award. REFERENCES 1. Somerville BW. The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology. 1972;22: Silberstein SD, Merriam GR. Estrogens, progestins, and headache. Neurology. 1991;41: Beckham JC, Krug LM, Penzien DB, et al. The relationship of ovarian steroids, headache activity and menstrual distress: a pilot study with female migraineurs. Headache. 1992;32: Epstein MT, Hockaday JM, Hockaday TD. Migraine and reproductive hormones throughout the menstrual cycle. Lancet. 1975;1: Nattero G, Bisbocci D, Ceresa F. Sex hormones, prolactin levels, osmolarity and electrolyte patterns in menstrual migraine relationship with fluid retention. Headache. 1979;19: Woods NF. Relationship of socialization and stress to perimenstrual symptoms, disability, and menstrual attitudes. Nurs Res. 1985;34: Holm JE, Bury L, Suda KT. The relationship between stress, headache, and the menstrual cycle in young female migraineurs. Headache. 1996;36:

9 Headache Brace M, McCauley E. Oestrogens and psychological well-being. Ann Med. 1997;29: Dennerstein L, Spencer-Gardner C, Gotts G, Brown JB, Smith MA, Burrows GD. Progesterone and the premenstrual syndrome: a double blind crossover trial. Br J Clin Res Educ. 1985;290: Rubinow DR, Schmidt PJ, Roca CA. Estrogenserotonin interactions: implications for affective regulation. Biol Psychiatry. 1999;44: Summer BE, Fink G. Estrogen increases the density of 5-hydroxytryptamine(2A) receptors in cerebral cortex and nucleus accumbens in the female rat. J Steroid Biochem Mol Biol. 1995;54: Martin VT, Wernke S, Zomma W, Mandell K, Liu J, Rebar R. Does the phase of the menstrual cycle have an influence on headache severity and disability in female migraineurs? [Abstract] Headache. 2000;5: Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology. 2001;56:S20- S International Headache Society Subcommittee. The international classification of headache disorders. Cephalalgia. 2004;24: Penzien DB, Andrew ME, Knowlton GE, et al. Computer-aided system for headache diagnosis with the HIS headache diagnostic criteria: development and validation. Cephalalgia. 1991;11(suppl 11): Andrew ME, Penzien DB, Rains JC, Knowlton GE, McAnulty RD. Development of a computer application for headache diagnosis: the Headache Diagnostic System. Int J Biomed Comput. 1992;31: Moos RH. The development of a menstrual distress questionnaire. Psychosom Med. 1968;38: Boyle GJ. Factor structure of the menstrual distress questionnaire (MDQ): exploratory and LIS- REL analyses. Pers Individ Dif. 1992;13: Moos RH. Perimenstrual Symptoms: A Manual and Overview of Research with the Menstrual Distress Questionnaire. Palo Alto, CA: Department of Psychiatry and Behavioral Sciences, Stanford University, Stewart WF, Lipton RB, Whyte J, et al. An international study to assess the reliability of the migraine disability assessment (MIDAS) score. Neurology. 1999;53: Jacobson GP, Ramadan NM, Aggarwal SK, Newman CW. The Henry Ford Hospital headache disability inventory (HDI). Neurology. 1994;44: Silberstein S, Merriam G. Sex hormones and headache 1999 (menstrual migraine). Neurology. 1999;53(suppl 1):S3-S13.