Platelet serotonin pathway in menstrual migraine

In order to understand the possible 5-hydroxytryptamine (5HT) anomalies in migraine, particularly in the period before the headache attack, we compared the levels of 5HT, its stable metabolite 5-hydroxyindoleacetic acid (5HIAA) and platelet monoaminoxidase (MAO) activity in patients with menstrual migraine with those of healthy female controls. In every subject, blood samples were drawn during both follicular and late luteal phases of the menstrual cycle. In controls, platelet 5HT levels remained stable, whereas 5HIAA levels and MAO activity were higher in the luteal than in the follicular phase, suggesting an increased catabolism of 5HT which occurs physiologically just before menses. In menstrual migraine 5HIAA levels and MAO activity showed similar changes with higher values in the luteal than in the follicular phase. The luteal phase values were significantly higher than those of controls. Also, and in contrast to controls, 5HT levels decreased in the luteal phase. These data suggest that 5HT availability is reduced in menstrual migraine, possibly due to an increased catabolism and/or to a reduced synthesis, and hence predisposes patients to migraine attacks.     

Relationship between precipitating agents and neurophysiological abnormalities in migraine

The particular mechanisms of migraine anticipation by different precipitating agents are still unknown. The contingent negative variation (CNV) was recorded in the premenstrual and ovulation phases of the cycle in both rest and stress conditions in 17 migraine and 15 healthy women. In migraineurs a significant increase of amplitude of the initial CNV component in the premenstrual phase compared with ovulation was observed. During both the ovulation and premenstrual phases both migraineurs and controls demonstrated a significant increase of the CNV amplitude on stress. The increase of the amplitude on stress in the premenstrual phase was more pronounced in migraineurs. This study shows that stress and menstrual cycle are associated with changes of the initial CNV amplitude, probably indicating a higher probability of migraine attacks.     

Hormones, menstrual distress, and migraine across the phases of the menstrual cycle

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.     

The Relationship of Ovarian Steroids, Headache Activity and Menstrual Distress: A Pilot Study With Female Migraineurs

Fourteen female volunteers who met diagnostic criteria for migraine headache monitored their headache activity and menstrual distress symptoms for one menstrual cycle. Serum estradiol and progesterone levels, and menstrual distress measures were collected at four points of the menstrual cycle: menstrual, ovulatory, luteal and premenstrual. Results indicated that one patient (7.1%) had menstrual migraine, 10 patients (71.4%) had menstrually-related headache and 3 (21.4%) had migraine headache unrelated to their menstrual cycle: subsequent analyses were conducted with the first two groups. Headache activity for the sample was highest during the premenstrual phase. Headache activity during the luteal and premenstrual phases was related to luteal phase progesterone levels. Menstrual distress was highest during the menstrual and premenstrual phases of the cycle, and these symptoms were related to higher estradiol levels, higher estradiol/progesterone ratios, and increased headache activity. These results indicated that for women with menstrual migraine or menstrually-related migraine, luteal progesterone and estradiol and the estradiol/progesterone ratio may be significantly related to menstrual distress during the premenstrual phase of the cycle. The estradiol/progesterone ratio was not more related to headache or menstrual distress than either of these ovarian hormones alone. Suggestions for future research in this area are offered.     

Migraine Chronobiology

This study was undertaken to determine whether migraine attacks exhibit circadian, menstrual, or seasonal variations in frequency and, thus, to characterize more precisely this relapsing, remittent pleomorphic disease. An analysis of 3582 well-documented migraine attacks in 1698 adults was undertaken. The demographics of the study population accurately represented the known epidemiology of the disease. Migraine attacks started more frequently between 4 am and 9 am and within the first few days after onset of menses; this migraine periodicity is strongest amongst women not using oral contraceptives. Seasonal periodicity, if any, is clearly weaker than circadian or menstrual. These chronobiological features may assist in the differential diagnosis of migraine from premenstrual headache and fibromyalgia.     

The association of menstrual migraine with the premenstrual syndrome

To investigate the comorbidity of premenstrual syndrome (PMS) and menstrual migraine, the Menstrual Distress Questionnaire (MDQ) was prospectively administered for two consecutive menstrual cycles to 22 patients with menstrual migraine, 12 cases with migraine without aura and 15 patients with PMS. MDQ scores varied throughout the menstrual cycle in each patient group, the wider changes being shown by patients with PMS. Fourteen menstrual migraine patients and 4 migraine without aura patients achieved diagnostic criteria for PMS over two menstrual cycles. In these patients MDQ scores did not differ from PMS sufferers at any stage of the menstrual cycle. The premenstrual increase of each cluster of PMS symptoms was identical in menstrual migraine and PMS subjects with the exception of negative affect. We suggest that PMS symptoms should be taken into account in the IHS diagnostic criteria for menstrual migraine.     

Alcohol effects on luteinizing hormone releasing hormone-stimulated anterior pituitary and gonadal hormones in women

Plasma luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, estradiol (E2) and progesterone were measured in 24 normal, adult women before and after i.v. administration of 100 micrograms luteinizing hormone releasing hormone (LHRH; Factrel) and p.o. ingestion of an alcohol (0.694 g of alcohol per kg b.wt.) or placebo solution. Twelve subjects were studied during the early follicular phase of the menstrual cycle and 12 subjects were studied during the midluteal phase of the menstrual cycle. During each menstrual cycle phase, six subjects received placebo solution and six subjects received alcohol solution administered under double-blind conditions. Mean peak blood alcohol levels of 113 to 122 mg/dl were measured 45 to 60 min after initiation of alcohol intake. LHRH stimulated a significant increase in LH after both alcohol (P less than .0001) and placebo (P less than .0001) administration, and this LH increase was equivalent during the follicular and the luteal phases of the menstrual cycle. LHRH also stimulated a significant increase in FSH levels after both alcohol and placebo intake during the follicular and luteal phases of the menstrual cycle (P less than .0001). There were no significant differences in LHRH-stimulated FSH between the alcohol and placebo conditions. Plasma prolactin levels also increased significantly after LHRH administration during the follicular and luteal phases of the menstrual cycle (P less than .0001). There were no significant differences in prolactin response to LHRH administration between the alcohol or placebo conditions during the follicular and luteal phases of the menstrual cycle. Plasma E2 levels did not increase significantly after LHRH administration and placebo alcohol during the follicular phase of the menstrual cycle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolism and Menstrual Cycle Rhythmicity of Serotonin in Primary Headaches

We investigated the platelet and plasma levels of serotonin and its metabolite, 5-hydroxyindoleacetic acid, in patients suffering from episodic tension-type headache and migraine with and without aura, during headache-free period. In female subjects, blood samples were drawn during the follicular, ovulatory, and late luteal phases of the menstrual cycle. In tension headache and migraine with aura, the group mean values of serotonin and 5-hydroxyindoleacetic acid in platelets and plasma were significantly increased, but migraine without aura patients' levels were normal. The pattern of menstrual cycle-related fluctuations in platelet serotonin levels were similar in female patients with tension headache and in controls, with a maximum value in the follicular phase. In both migraine groups, in contrast, the peak occurred in the ovulatory phase. The results are discussed in view of whether these aberrations in peripheral markers of the metabolism and menstrual cycle-related rhythmicity of serotonin may reflect similar alterations in the central nervous system.     

Magnesium Prophylaxis of Menstrual Migraine: Effects on Intracellular Magnesium

The effects of oral Magnesium (Mg) pyrrolidone carboxylic acid were evaluated in 20 patients affected by menstrual migraine, in a double-blind, placebo controlled study. After a two cycles run-in period, the treatment (360 mg/day of Mg or placebo) started on the 15th day of the cycle and continued till the next menses, for two months. Oral Mg was then supplemented in an open design for the next two months. At the 2nd month, the Pain Total Index was decreased by both Placebo and Mg, with patients receiving active drug showing the lowest values (P less than 0.03). The number of days with headache was reduced only in the patients on active drug. Mg treatment also improved premenstrual complaints, as demonstrated by the significant reduction of Menstrual Distress Questionnaire (MDQ) scores. The reduction of PTI and MDQ scores was observed also at the 4th month of treatment, when Mg was supplemented in all the patients. Intracellular Mg++ levels in patients with menstrual migraine were reduced compared to controls. During oral Mg treatment, the Mg++ content of Lymphocytes (LC) and Polymorphonucleated cells (PMN) significantly increased, while no changes in plasma or Red Blood Cells were found. An inverse correlation between PTI and Mg++ content in PMN was demonstrated. These data point to magnesium supplementation as a further means for menstrual migraine prophylaxis, and support the possibility that a lower migraine threshold could be related to magnesium deficiency.     

Homocysteine during the menstrual cycle in depressive women

BACKGROUND: Two possible factors that may have a causal relation with both depressive disorder and cardiovascular disease are elevated homocysteine and steroid hormones. Our previous study found significant changes in the plasma homocysteine concentration during the menstrual cycle in healthy women. The purpose of this study therefore was to test homocysteine in depressive women treated with fluoxetine during the menstrual cycle. MATERIALS AND METHODS: Thirteen premenopausal women suffering from mixed anxiety-depressive disorder and a control group of 15 healthy women were enrolled in this study. The homocysteine concentration was determined by high-performance liquid chromatography with fluorescence detection, and estradiol, progesterone and cortisol by RIA methods. RESULTS: We found significantly higher plasma homocysteine concentrations in the follicular phase than in the luteal phase of the menstrual cycle in both the depressive group (P < 0.003) and the controls (P < 0.0009). Moreover, the patient values of total homocysteine were significantly higher in the follicular phase (P < 0.03) and also in the luteal phase (P < 0.007) than the values of the controls. Estradiol and cortisol were significantly higher in the follicular phase of the patients compared with the control group. CONCLUSION: According to our results, women suffering from mixed anxiety-depressive disorder have not only significantly different concentrations of homocysteine in the follicular and luteal phase of the menstrual cycle but also higher plasma homocysteine compared with healthy women. More elevated homocysteine in the depressive than in the healthy premenopausal women points to the notion that psychological factors might be important when considering the homocysteine concentration.     

Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres

Aim of this study was to determine whether menstrual attacks differ from nonmenstrual attacks (NMA) as regards clinical features or response to abortive treatment in women affected by menstrually related migraine (MRM) referred to tertiary care centres. Sixty-four women with MRM were enrolled in a 2-month diary study. Perimenstrual attacks were split into three groups--premenstrual (PMA), menstrual (MA) and late menstrual (LMA)--and compared to nonmenstrual ones. Perimenstrual attacks were significantly longer than NMA. No other migraine attack features were found to differ between the various phases of the cycle. Migraine work-related disability was significantly greater in PMA and MA than in NMA. Acute attack treatment was less effective in perimenstrual attacks. Pain-free at 2 h after dosage was achieved in 13.5% of MA (OR 0.41; 95% CI 0.22, 0.76) vs. 32.9% of NMA. We concluded that, in MRM, perimenstrual attacks are longer and less responsive to acute attack treatment than NMA.     

MENSTRUAL MIGRAINE

Aim of this study was to determine whether menstrual attacks differ from nonmenstrual attacks (NMA) as regards clinical features or response to abortive treatment in women affected by menstrually related migraine (MRM) referred to tertiary care centres. Sixty-four women with MRM were enrolled in a 2-month diary study. Perimenstrual attacks were split into three groups—premenstrual (PMA), menstrual (MA), and late menstrual (LMA)—and compared to nonmenstrual ones. Perimenstrual attacks were significantly longer than NMA. No other migraine attack features were found to differ between the various phases of the cycle. Migraine work-related disability was significantly greater in PMA and MA than in NMA. Acute attack treatment was less effective in perimenstrual attacks. Pain-free at 2 hours after dosage was achieved in 13.5% of MA (OR 0.41; 95% CI 0.22, 0.76) versus 32.9% of NMA. We concluded that, in MRM, perimenstrual attacks are longer and less responsive to acute attack treatment than NMA.     

Corticotropin-Releasing Hormone and Opioid Peptides in Reproduction and Stress

Increased knowledge on the mechanisms whereby corticotropin releasing hormone (CRH) and opioid peptides mediate the effects of stress has helped us to understand the relationship between stress and disturbed reproductive function. Increases of CRH and β-endorphin in the hypothalamus in stressful situations inhibits the secretion of gonadotropins, oxytocin and vasopressin. This may lead to amenorrhea, which often is a consequence of intensive training or psychological stress, or it may disrupt parturition and lactation. There is a relationship between ovarian function and opioid peptides in the hypothalamus. Opioid peptides increase during puberty and fall at the menopause. Oestradiol and progesterone increase β-endorphin concentrations in the luteal phase of the menstrual cycle, and this is followed by a rapid fall at menstruation. These changes may mediate symptoms typical of the premenstrual syndrome. Rather intensive exercise is required to increase plasma concentrations of β-endorphin and corticotropin. During labour the amounts of β-endorphin and corticotropin reach the values found in athletes during maximal exercise. The placenta produces increasing amounts of CRH towards the end of pregnancy which may help the mother and fetus to withstand the increased demands of labour. The placenta may thus be involved in the adaptation of the stress mechanism during pregnancy. CRH has also a paracrine function in different biological processes of the placenta and fetal membranes. It is possible to counteract the deleterious effects of stress on reproductive function by the administration of opiate antagonists. Induction of ovulation with naltrexone has been shown in patients with hypothalamic amenorrhea but the effect on fertility is not known.     

Vitamin D and Calcium in Menstrual Migraine

SYNOPSIS
Two premenopausal women with a history of menstrually-related migraines and premenstrual syndrome were treated with a combination of vitamin D and elemental calcium for late luteal phase symptoms. Both cited a major reduction in their headache attacks as well as premenstrual symptomatology within 2 months of therapy. These observations suggest that vitamin D and calcium therapy should be considered in the treatment of migraine headaches.     

Menstrual migraine in a representative Dutch population sample: prevalence,disability and treatment

We assessed the prevalence of menstrual migraine and its restrictions on daily activities in a representative Dutch population sample of 1181 Dutch women, aged 13-55 years. Further, we evaluated the potential role of oral contraceptives, and how menstrual migraine is treated. More than half suffered from menstrual complaints, a substantial proportion reported headache or migraine as a frequent problem. Use of oral contraceptives seemed to reduce the occurrence of menstrual complaints, but not the occurrence of headache and migraine. In our study, the prevalence of menstrual migraine (3%) is lower than in the literature, most probably because we did not use a selected group of patients but a population-based sample of ordinary women. It was confirmed that attacks of menstrual migraine are more severe, of longer duration, and more resistant to treatment than migraine attacks at other times of the month.     

Muscle tension and its relation to symptoms in the premenstruum

Muscle tension as a function of sympathetic arousal may play a causal or contributory role in symptomatology in the premenstruum. The purpose of this study was to determine whether women exhibit an increase in muscle tension in the premenstrual phase over that in the follicular phase of the menstrual cycle, and whether the incidence and severity of premenstrual symptoms were associated with premenstrual muscle tension. A sample of 22 women with variable levels of predicted premenstrual symptomatology was chosen. A report of symptoms was obtained in the premenstrual and follicular phases of the menstrual cycle. Frontalis and trapezius muscle tension levels also were obtained during these cycle phases, during relaxation, and during focus on an emotional image. A difference was found in the subjects' premenstrual and follicular phase frontalis electromyogram (EMG) levels both in the initial relaxation period and while focusing on an emotional image. A significant positive correlation was found between the premenstrual physiologic symptoms women predicted they would have and the premenstrual frontalis EMG levels measured during relaxation. The results suggest that training in muscle tension reduction may benefit premenstrual symptoms.     

Characteristics of Menstrual vs Nonmenstrual Migraine: A Post Hoc,Within‐Woman Analysis of the Usual‐Care Phase of a Nonrandomized Menstrual Migraine Clinical Trial

Objective.— To compare, using a within‐woman analysis, the severity, duration, and relapse of menstrual vs nonmenstrual episodes of migraine during treatment with usual migraine therapy. Background.— Studies comparing the clinical characteristics of menstrual and nonmenstrual migraine attacks have yielded conflicting results, contributing to disagreement regarding whether menstrual migraine attacks are clinically more problematic than nonmenstrual migraine attacks. Methods.— Post hoc within‐woman analysis of the usual‐care phase (month 1) of a 2‐month, multicenter, prospective, open‐label study at 21 US medical practices (predominantly primary care). Participants were women ≥18 years of age with regular predictable menstrual cycles (28 ± 4 days) who self‐reported a ≥1‐year history of migraine attacks occurring between days ?2 and +3 (menses onset = day +1) and ≥8 such attacks within the previous 12 cycles. Migraine treatment episodes were categorized as menstrual (occurring on days ?2 to +3 of menses) or nonmenstrual (occurring on days +4 to ?3 of menses). Pain severity, functional impairment, duration, relapse in 24 hours, and use of rescue medication were compared. Sources of variability (within‐ or between‐patient) were determined using mathematical modeling. The http://www.clinicaltrial.gov code for trial is NCT00904098. Results.— Women (n = 153; intent to treat) reported 212 menstrual (59.2%) and 146 nonmenstrual (40.8%) migraine treatment episodes. Compared with nonmenstrual treatment episodes, menstrual episodes were more likely to cause impairment (unadjusted odds ratio, 1.65, 95% CI, 1.05‐2.60; P = .03), were longer (unadjusted hazard ratio 1.68; 95% CI, 1.31‐2.16; P < .001), and were more likely to relapse within 24 hours (unadjusted odds ratio, 2.66; 95% CI, 1.25‐5.68; P = .01). Within‐patient effects accounted for only 18‐33% of the total variance in these outcomes. Conclusions.— Post hoc, within‐woman analysis of migraine treatment episodes categorized based on International Headache Society criteria showed that menstrual treatment episodes were more impairing, longer lasting, and more likely to relapse than nonmenstrual treatment episodes in this selected population of women with frequent menstrual migraine. The current analysis indicates that most of the variability in these outcomes is due to differences between headache types and not within‐patient differences for a given type of headache, suggesting that menstrual episodes are potentially treatable. These findings underscore the differences between menstrual and nonmenstrual episodes of migraine and the need to offer effective migraine treatment to women. (Headache 2010;50:528‐538)     

Disability associated with headaches occurring inside and outside the menstrual period in those with migraine: a general practice study

Objectives.—This study investigated the disability of females who have migraine and other headache attacks occurring during and outside the menstrual period.
Methods.—One thousand four hundred and thirty-four of 3470 female patients (41.3%) aged 14 to 50 years registered at a UK general practice completed two questionnaires. The first questionnaire assessed the prevalence of headache, depression, and bodily pain in the total population. The second questionnaire assessed the disability of all headaches over a 2-month period (to capture a complete menstrual cycle) for patients reporting migraine who were still menstruating. Disability was assessed as the time lost and time spent at less than 50% productivity in normal activities due to headache, and analyzed as rank sums using the Mann-Whitney U -test.
Results.—The first part of the study showed that the prevalence of headache (66.1%), depression (55.4%), and bodily pain (40.6%) were high in this population of women. Thirty migraine patients who were still menstruating reported 89 migraine and 114 nonmigraine headache episodes in the second part of the study. For migraine, the rank order of time at less than 50% productivity was greater for attacks taking place inside the menstrual period than for those occurring outside the menstrual period. The comparison was significant for time at less than 50% productivity ( P = .01). For nonmigraine headaches, the rank order of time lost was greater for attacks taking place outside the menstrual period than for those occurring inside the menstrual period. The comparison was not significant for time lost ( P = .06).
Conclusions.—For those with migraine, migraine attacks that took place during the menstrual period tended to be slightly more disabling than those taking place outside the menstrual period, but the opposite was true for nonmigraine headache.     

Changes of neuroendocrine axes in patients with menstrual migraine

Menstrual migraine (MM) is a menstrually related disorder (MRD) characterized by several symptoms in common with premenstrual syndrome (PMS). It has been hypothesized that in both MM and PMS hormonal cyclicity could change the balance of neurotransmitters and neuromodulators like monoamine and opioid. In this article we analyze all the data collected by our group on the central opioid tonus and the adrenergic and serotonergic systems in patients affected by menstrual migraine.     

Symptoms of premenstrual syndrome and their association with migraine headache

OBJECTIVES: To determine the association between the severity of premenstrual (PMS) symptoms and headache outcome measures during natural menstrual cycles and after medical oophorectomy. BACKGROUND: Premenstrual syndrome may occur in 64% of those with pure menstrual migraine and 33% of those with menstrually related migraine. Few past studies have examined the relationship between the severity of PMS symptoms and migraine headache. METHODS: Data were obtained from a 6.5-month randomized-controlled trial examining the role of medical oophorectomy in the prevention of migraine headache and later divided into two data sets for analysis purposes. The menstrual cycle data set was composed of data from three natural menstrual cycles obtained from 21 participants during lead-in and placebo run-in phases. Each menstrual cycle was subdivided into seven 3-day intervals based on urine hormone metabolites. The medical oophorectomy data set included data from a 2-month treatment period in which a medical oophorectomy was induced by gonadotropin-releasing hormone agonists (GnRHa) and participants were randomized to transdermal estradiol or a matching placebo (GnRHa/estradiol and GnRHa/placebo groups, respectively). All participants completed a daily diary recording the severity of PMS symptoms and headache outcome measures. The primary outcome measures were the PMS index (mean of the daily PMS severity scores) and the headache index (mean of the headache severity scores). Pearson correlation coefficients were used to assess the degree of association between the outcome measures. RESULTS: Menstrual Cycle Data Set.-The PMS index was significantly correlated with the headache index during native menstrual cycles (correlation coefficient of 0.47; P < .05) and during all seven intervals of the menstrual cycle (correlation coefficients of 0.39 to 0.65; all P values < .05). Medical Oophorectomy Data Set.-Correlation coefficients between the PMS and headache indices were 0.58 and 0.47 for the GnRHa/estradiol (n = 9) and GnRHa/placebo groups, respectively (P-values of <.05). CONCLUSIONS: Moderate correlations exist within female migraineurs between the severity of PMS symptoms and headache outcome measures throughout natural menstrual cycles as well as after medical oophorectomy. Our data would suggest that the presence and severity of headache might modulate PMS symptoms in female migraineurs.