Migraine and breast cancer risk: a meta-analysis of observational studies based on MOOSE compliant

AbstractIt has long been speculated that migraine may contribute to an increased risk of breast cancer; however, results from previous studies have been inconclusive. To definitively interrogate this issue, we performed a meta-analysis to assess the correlation between these 2 diseases.Medline and PubMed were searched to identify relevant studies that had been published until October 2015. Based on a random effects model, relative risk (RR) and the corresponding 95% confidence interval (CI) were used to evaluate the pooled risk.A total of 7 studies involving 17,776 cases and 162,954 participants were included. Our study revealed that there was an inverse relationship between migraine and total breast cancer risk, with RR (95%CI) was 0.78 (0.66, 0.92). In subgroup-analysis, such an inverse relationship was also identified in the ductal and lobular carcinoma, case–control studies, and the ER+/PR+ breast cancer. Little evidence indicative of a publication bias was uncovered.In conclusion, our study implicates a statistically significant inverse association between migraine and the risk of breast cancer. However, larger prospective cohort studies concerning other geographic populations to assess the association between migraine and the breast cancer risk are warranted.

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title: Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors.
abstract: To describe the magnitude and distribution of the public health problem posed by migraine in the United States by examining migraine prevalence, attack frequency, and attack-related disability by gender, age, race, household income, geographic region, and urban vs rural residence.



In 1989, a self-administered questionnaire was sent to a sample of 15,000 households. A designated member of each household initially responded to the questionnaire. Each household member with severe headache was asked to respond to detailed questions about symptoms, frequency, and severity of headaches.



A sample of households selected from a panel to be representative of the US population in terms of age, gender, household size, and geographic area.



After a single mailing, 20,468 subjects (63.4% response rate) between 12 and 80 years of age responded to the survey. Respondents and non-respondents did not differ by gender, household income, region of the country, or urban vs rural status. Whites and the elderly were more likely to respond. Migraine headache cases were identified on the basis of reported symptoms using established diagnostic criteria.



17.6% of females and 5.7% of males were found to have one or more migraine headaches per year. The prevalence of migraine varied considerably by age and was highest in both men and women between the ages of 35 to 45 years. Migraine prevalence was strongly associated with household income; prevalence in the lowest income group (less than $10,000) was more than 60% higher than in the two highest income groups (greater than or equal to $30,000). The proportion of migraine sufferers who experienced moderate to severe disability was not related to gender, age, income, urban vs rural residence, or region of the country. In contrast, the frequency of headaches was lower in higher-income groups. Attack frequency was inversely related to disability.



A projection to the US population suggests that 8.7 million females and 2.6 million males suffer from migraine headache with moderate to severe disability. Of these, 3.4 million females and 1.1 million males experience one or more attacks per month. Females between ages 30 to 49 years from lower-income households are at especially high risk of having migraines and are more likely than other groups to use emergency care services for their acute condition.

title: Effects of Ovarian Steroids and Raloxifene on Proteins that Synthesize, Transport, and Degrade Serotonin in the Raphe Region of Macaques
abstract: In the monkey dorsal raphe, we reported that 1-month (mo) of estrogen replacement, with or without progesterone supplementation for 14 days, significantly increased tryptophan hydroxylase-1 (TPH-1) mRNA; decreased serotonin reuptake transporter (SERT) mRNA and decreased monoamine oxidase (MAO)-A mRNA, but had no effect on MAO-B mRNA. Here, we questioned what effect would 1 or 5 mo of ovarian hormones or the selective estrogen receptor modulator (SERM), raloxifene, have on TPH protein and phosphorylation, and on protein expression of SERT, MAO-A or MAO-B? Raloxifene antagonizes estrogen in breast or uterus, but estrogen-like activities in the brain have been reported. Cytoplasmic and membrane extracts of the dorsal raphe region were processed for Western blotting. TPH, phosphoserine, SERT, MAO-A, and MAO-B were detected with specific antibodies. The optical densities of the signals were measured with NIH image and analyzed by ANOVA. Both 1 and 5 mo of estrogen, with or without progesterone, and 5 mo of raloxifene significantly increased TPH protein. Administration for 5 mo of estrogen plus progesterone and raloxifene also increased TPH phosphorylation. Estrogen, with or without progesterone, for 1 mo had no effect on SERT protein. However, 5 mo of estrogen and 5 mo of raloxifene increased SERT protein. Estrogen alone or combined with progesterone for 1 mo caused a significant reduction in MAO-A. Yet, after 5 mo of the same treatments, MAO-A was not different from spayed controls. Estrogen alone had no effect on MAO-B. However, the addition of progesterone significantly increased MAO-B. Raloxifene for 5 mo had no effect on MAO-A or MAO-B. Thus, to various extents, estrogen, progesterone, and raloxifene may increase serotonin production and transport. The expression of the degradative enzymes suggests a complex combination of gene transcription, post-transcriptional processing, and substrate feedback mechanisms.

title: Estrogens, Migraine, and Stroke
abstract: Epidemiological studies suggest the existence of close but complex relationships between estrogens, migraine, and stroke in women before menopause. Migraine, particularly without aura, is strongly influenced by estrogens as illustrated by the frequency of onset at puberty, of menstrual migraine, and of improvement during pregnancy. Migraine, particularly with aura, is a risk factor for ischemic stroke with a relative risk of 3, further increased by tobacco smoking and oral contraceptive use. The pathophysiological mechanism underlying these close relationships remains unknown. In practice, given the very low absolute risk of stroke in young women, there is no systematic contraindication to oral contraceptive use in young female migraineurs but rather a firm recommendation for no smoking and for the use of low-estrogen-content pills or progestogens only, particularly in migraine with aura.

title: Oestrogen and attacks of migraine with and without aura
abstract: During women's reproductive years, migraine is three times more common than in men of a similar age. Although this female preponderance is commonly assumed to be associated with the additional trigger of fluctuating sex hormones of the menstrual cycle, few studies have been done to confirm or refute this. This review is confined to the relation between oestrogen and attacks of migraine. The evidence for an association between oestrogen "withdrawal" and attacks of migraine without aura is presented, as well as evidence for an association between high oestrogen states and attacks of migraine with aura. Only clinical data are presented here.

title: Oral contraceptives in migraine therapy
abstract: Even if sometimes combined oral contraceptives (COCs) can initiate or aggravate headaches, in particular migraine, the headaches generally tend to improve after the first months of COC use. If migraine persists, in many patients the attacks are more likely to occur during the pill-free week, and an oral contraceptive-induced menstrual migraine (OCMM) occurs. In case of OCMM, some hormonal manipulations are available, by eliminating or reducing the hormone-free interval (HFI), in order to prevent this estrogen-withdrawal headache. It is possible to use a continuous COCs regimen, to shorten the HFI to less than the traditional 7 days, to use a low-dose estrogen supplementation after the 21 days of COCs or to prescribe a progestogen–only pill (POP). Interestingly, the use of a POP is a safe option also for women suffering from migraine with aura (in which COCs are absolutely contraindicated) and a recent trial suggests that its use can reduce the frequency of migraine attacks and the duration of aura symptoms too.

title: Headache During Gestation: Evaluation of 1101 Women
abstract: The purpose of this study was to evaluate the presence of headache in women with a previous history or new-onset headache during the current gestation, classify the findings, and describe the clinical characteristics and outcome of the headache.  From January/1998 to June/2002 we prospectively evaluated 1101 pregnant women (12-45 years old), with a history of headache, at two prenatal clinics and an inpatient obstetric public hospital. Women were interviewed using a semi-structured questionnaire during the first, second, and third gestation trimesters and immediately after delivery. All interviews were conducted by one of the authors, using the International Headache Society Classification (IHSC-2004).  In 1029 women there was a history of headache prior to the current pregnancy, 36 (3.4%) women first experienced headache during this pregnancy and 40 patients experienced new types of headache. In these 76 patients with new onset headache during pregnancy, 40 had secondary headache (52.6%), 31 had primary headache (40.8%), and 5 had headache not classified elsewhere (6.6%). According to IHSC- 2004 criteria, we found migraine in 848/1029 women (82.4%), with pregestational headache.  Most of the pregnant women presented with headache, mainly in migraine, prior to pregnancy, and most of the headaches improved or disappeared during the second and third gestation trimester. In a relatively small number of pregnant women, a new type of headache started during the gestation.

title: Treatment results and prognostic factors of early breast cancer treated with a breast conserving operation and radiotherapy.
abstract: The purpose of this study was to analyze the prognostic factors affecting local control and survival rates for patients with early breast cancer who received breast conserving treatment (BCT) and to find out the optimal treatment according to their risk factors.



From October 1994 to December 2001, 605 patients with 611 stage I and II breast cancers received BCT, and the results were analyzed retrospectively. BCT consists of breast conserving surgery and whole breast irradiation. All the patients underwent lumpectomy or quadrantectomy. Axillary lymph node dissection or sentinel lymph node biopsy was performed in 608 cases (99.5%). The radiation dose to the whole breast was 50.4 Gy over 5 weeks with a 1.8 Gy daily fraction and with boost doses of 9-14.4 Gy administered to the tumor bed. Adjuvant chemotherapy was performed in most of the patients with axillary lymph node metastasis or tumors larger than 1 cm. The median follow-up period was 47 months.



Local relapse, regional relapse and distant metastasis occurred in 15 (2.5%), 16 (2.6%) and 43 patients (7.1%), respectively. The 5-year overall survival, local-relapse-free survival, distant-metastasis-free survival and disease-free survival rates were 95.3%, 97.2%, 91.3% and 88.5%, respectively. On multivariate analysis, age (P = 0.02), number of involved axillary lymph nodes (P = 0.01) and nuclear grade (P = 0.01) affected the local-relapse-free survival. The factors associated with disease-free survival were the T stage (P = 0.05), number of involved axillary lymph nodes (P = 0.01) and nuclear grade (P = 0.001). Overall survival was associated with the T stage (P = 0.02), number of involved axillary lymph nodes (P = 0.01) and c-erb B2 overexpression (P = 0.05). Patients with more than two factors among (i) age </=35 years, (ii) positive lymph node metastasis and (iii) high nuclear grade showed a poor 5-year local-relapse-free survival rate compared with others (P = 0.001). Also, patients with more than two factors among (i) tumor size >1 cm, (ii) positive lymph node metastasis and (iii) high nuclear grade showed an inferior 5-year disease-free survival rate compared with others (P = 0.0005).



The most important prognostic factor affecting local control, disease-free survival and overall survival was axillary lymph node metastasis. The nuclear grade influenced local control and disease relapse. Patients with multiple unfavorable risk factors such as positive axillary lymph nodes, high nuclear grade, young age and large tumor showed poorer local control and disease-free survival than patients without any risk factors, and so more aggressive treatment is required for these patients.

title: Etiology of hormone receptor-defined breast cancer: a systematic review of the literature.
abstract: Breast cancers classified by estrogen receptor (ER) and/or progesterone receptor (PR) expression have different clinical, pathologic, and molecular features. We examined existing evidence from the epidemiologic literature as to whether breast cancers stratified by hormone receptor status are also etiologically distinct diseases. Despite limited statistical power and nonstandardized receptor assays, in aggregate, the critically evaluated studies (n = 31) suggest that the etiology of hormone receptor-defined breast cancers may be heterogeneous. Reproduction-related exposures tended to be associated with increased risk of ER-positive but not ER-negative tumors. Nulliparity and delayed childbearing were more consistently associated with increased cancer risk for ER-positive than ER-negative tumors, and early menarche was more consistently associated with ER-positive/PR-positive than ER-negative/PR-negative tumors. Postmenopausal obesity was also more consistently associated with increased risk of hormone receptor-positive than hormone receptor-negative tumors, possibly reflecting increased estrogen synthesis in adipose stores and greater bioavailability. Published data are insufficient to suggest that exogenous estrogen use (oral contraceptives or hormone replacement therapy) increase risk of hormone-sensitive tumors. Risks associated with breast-feeding, alcohol consumption, cigarette smoking, family history of breast cancer, or premenopausal obesity did not differ by receptor status. Large population-based studies of determinants of hormone receptor-defined breast cancers defined using state-of-the-art quantitative immunostaining methods are needed to clarify the role of ER/PR expression in breast cancer etiology.

title: Migraine in Postmenopausal Women and the Risk of Invasive Breast Cancer
abstract: The frequency of migraine headache changes at various times of a woman's reproductive cycle. Menarche, menses, pregnancy, and perimenopause may carry a different migraine risk conceivably because of fluctuating estrogen levels, and in general, migraine frequency is associated with falling estrogen levels. Given the strong relationship between endogenous estrogen levels and breast cancer risk, migraine sufferers may experience a reduced risk of breast cancer.  We combined data from two population-based case-control studies to examine the relationship between migraine and risk of postmenopausal invasive breast cancer among 1,199 ductal carcinoma cases, 739 lobular carcinoma cases, and 1,474 controls 55 to 79 years of age. Polytomous logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI).  Women who reported a clinical diagnosis of migraine had reduced risks of ductal carcinoma (OR, 0.67; 95% CI, 0.54-0.82) and lobular carcinoma (OR, 0.68; 95% CI, 0.52-0.90). These associations were primarily limited to hormone receptor–positive tumors as migraine was associated with a 0.65-fold (95% CI, 0.51-0.83) reduced risk of estrogen receptor–positive (ER+)/progesterone receptor–positive (PR+) ductal carcinoma. The reductions in risk observed were seen among migraine sufferers who did and did not use prescription medications for their migraines.  These data suggest that a history of migraine is associated with a decreased risk of breast cancer, particularly among ER+/PR+ ductal and lobular carcinomas. Because this is the first study to address an association between migraine history and breast cancer risk, additional studies are needed to confirm this finding.

title: Relationship between Migraine History and Breast Cancer Risk among Premenopausal and Postmenopausal Women
abstract: Both migraine and breast cancer are hormonally mediated diseases, and it is biologically plausible that women with a history of migraine may have a reduced breast cancer risk. However, this relationship has only been assessed in a single relatively small study that was unable to assess the effect of migraine triggers, which are also well-established breast cancer risk factors (e.g., use of alcohol and exogenous hormones), on the inverse association observed. Utilizing data on 4,568 breast cancer cases and 4,678 controls who participated in a multicenter population-based case-control study in the United States, we evaluated the association between migraine history and breast cancer risk using unconditional logistic regression. Migraine history data were obtained from structured in-person interviews. Women with a history of migraine had a reduced risk of breast cancer [odds ratio, 0.74; 95% confidence interval (CI), 0.66-0.82]. This risk did not differ by menopausal status, age at migraine diagnosis, use of prescription migraine medications, or when analyses were restricted to women who avoided various migraine triggers (including alcohol, exogenous hormones, and smoking). These data support a previous finding that a history of migraine may be associated with a reduced risk of breast cancer. It extends the prior report in observing that this relationship holds for both premenopausal and postmenopausal women and is independent of exposure to common migraine triggers.

title: Migraine history and breast cancer risk among postmenopausal women.
abstract: Both migraine and breast cancer are hormonally mediated. Two recent reports indicate that women with a migraine history may have a lower risk of postmenopausal breast cancer than those who never suffered migraines. This finding requires confirmation; in particular, an assessment of the influence of use of nonsteroidal anti-inflammatory drugs (NSAID) is needed, because many studies indicate that NSAID use also may confer a reduction in breast cancer risk.  We assessed the relationship between self-reported history of migraine and incidence of postmenopausal breast cancer in 91,116 women enrolled on the Women's Health Initiative Observational Study prospective cohort from 1993 to 1998 at ages 50 to 79 years. Through September 15, 2005, there were 4,006 eligible patients with breast cancer diagnosed.  Women with a history of migraine had a lower risk of breast cancer (hazard ratio [HR], 0.89; 95% CI, 0.80 to 98) than women without a migraine history. This risk did not vary by recent NSAID use. The lower risk was somewhat more pronounced for invasive estrogen-receptor-positive and progesterone-receptor-positive tumors (HR, 0.83; 95% CI, 0.71 to 0.97), as no reduction in risk was observed for invasive ER-negative/PR-negative tumors (HR, 1.16; 95% CI, 0.86 to 1.57), and this difference in risk estimates was borderline statistically significant (P = .06).  This study supports the hypothesis that a history of migraine is associated with a lower risk of breast cancer and that this relationship is independent of recent NSAID use.

title: Migraine and subsequent risk of breast cancer: a prospective cohort study
abstract: PurposePrevious studies have suggested that migraineurs are at decreased risk for developing breast cancer. Further prospective studies are warranted to confirm these results. In addition, studies evaluating migraine characteristics (e.g., migraine subtypes and frequency) are lacking.MethodsWe conducted a prospective cohort study among 39,696 participants in the Women’s Health Study who were 45 years and older at study entry. Information on migraine was self-reported with good validation rates. Incident breast cancer cases were confirmed by medical record review. We distinguished the following major endpoints: any breast cancer, a combined endpoint of invasive and in situ cases, in situ breast cancer only, and invasive breast cancer only. Cox proportional hazards models were used to calculate age- and multivariable-adjusted hazard ratios (HRs) and 95 % confidence intervals (95 % CI).ResultsA total of 7,318 (18.4 %) women reported any migraine. During a mean follow-up time of 13.6 years, 432 in situ and 1,846 invasive breast cancer cases occurred. Migraine was not associated with breast cancer risk. The multivariable-adjusted HRs (95 % CI) were 1.10 (0.99–1.22) for any breast cancer, 1.06 (0.83–1.35) for in situ breast cancer, and 1.11 (0.99–1.25) for invasive breast cancer. The risk for developing breast cancer differed according to hormone receptor status with a suggestion of increased risks for hormone receptor negative tumors (HR ER−/PR− : 1.28, 95 % CI: 0.96–1.71). We did not observe meaningful differences with regard to histologic subtype or according to migraine aura status or migraine attack frequency.ConclusionsResults of our study do not support the hypothesis that migraineurs have a decreased risk for breast cancer.

title: The risk of breast cancer associated with specific patterns of migraine history
abstract: AbstractPurpose
Studies have suggested that a history of migraines may be associated with a lower risk of some types of breast cancer, though biological mechanisms are unclear. Identifying specific characteristics of migraines which are most strongly associated with breast cancer risk could improve our understanding of this relationship.
We ascertained specific characteristics of women’s migraine histories (severity, timing features, and presence of migraine aura). We used polytomous logistic regression to estimate the risk of ER+ ductal, ER− ductal, ER+ lobular, and ER+ ductal–lobular breast cancer associated with self-reported characteristics of migraine history. A total of 715 breast cancer cases (276 ER+ ductal, 46 ER− ductal, 191 ER+ lobular, and 202 ER+ ductal–lobular) and 376 controls ages 55–74 years were included in this population-based case–control study.ResultsCompared to women without a migraine history, women with a >30-year history of migraines had a 60 % (95 % CI 0.2–0.6) lower risk of ER+ ductal breast cancer; those who had their first migraine before age 20 had 50 % lower risks of ER+ ductal and ER+ lobular breast cancer (both 95 % CIs 0.3–0.9), and women who experienced migraine with aura had 30 % (95 % CI 0.5–0.98) and 40 % (95 % CI 0.4–0.9) lower risks of ER+ ductal and ER+ lobular breast cancer, respectively.ConclusionThe lower risk of ER+ breast cancer associated with migraine appears to be limited to those women with early onset or long duration of migraine history, or those who experienced migraine with aura. This expands our understanding of the relationship between migraine and breast cancer and provides additional insight into potential underlying biological mechanisms.

title: Meta-analysis in clinical trials.
abstract: This paper examines eight published reviews each reporting results from several related trials. Each review pools the results from the relevant trials in order to evaluate the efficacy of a certain treatment for a specified medical condition. These reviews lack consistent assessment of homogeneity of treatment effect before pooling. We discuss a random effects approach to combining evidence from a series of experiments comparing two treatments. This approach incorporates the heterogeneity of effects in the analysis of the overall treatment efficacy. The model can be extended to include relevant covariates which would reduce the heterogeneity and allow for more specific therapeutic recommendations. We suggest a simple noniterative procedure for characterizing the distribution of treatment effects in a series of studies.

title: Migraine and breast cancer risk: a prospective cohort study and meta-analysis.
abstract: The evidence for an association between migraine and breast cancer risk is inconclusive. While female sex hormones have been proposed as one underlying mechanism, data on sex hormone levels in migraineurs are sparse.



We prospectively evaluated the association between migraine and breast cancer risk among 115378 Nurses' Health Study II participants using Cox proportional hazards models. Differences in endogenous sex hormone levels according to migraine status were assessed among 2034 premenopausal women using linear regression. We performed a meta-analysis of studies investigating the association between migraine and invasive breast cancer risk published through October 2013. All statistical tests were two-sided.



Seventeen thousand six hundred ninety-six women (15.3%) reported a physician's diagnosis of migraine at baseline. Over 20 years of follow-up, 833 in situ and 3091 invasive breast malignancies occurred. Migraine was not associated with total (hazard ratio [HR] = 0.96, 95% confidence interval [CI] = 0.88 to 1.04), in situ (HR = 0.97, 95% CI = 0.82 to 1.15), or invasive breast cancer risk (HR = 0.95, 95% CI = 0.87 to 1.04). Endogenous sex hormone levels did not differ according to migraine status. In the meta-analysis, migraine was associated with a lower risk of breast cancer overall (pooled risk ratio [RR] = 0.84, 95% CI = 0.73 to 0.98). However, this inverse association was apparent only among case-control studies (pooled RR = 0.72, 95% CI = 0.66 to 0.79), and not among cohort studies (pooled RR = 0.98, 95% CI = 0.87 to 1.10).



In this large cohort study, migraine was not associated with breast cancer risk or differences in endogenous sex hormone levels. While case-control studies suggest an inverse association between migraine and breast cancer risk, prospective cohort studies do not support an association in pooled analyses.

title: Evaluation of relationship between breast cancer and migraine
abstract: Frequency of migraine changes at different times of a woman′s reproductive cycle because of fluctuation of estrogen levels. Breast cancer has also a link with hormonal changes. Given this fact that both migraine and breast cancer are affected by estrogen, the prevalence of migraine may be different in breast cancer patients compared to the normal population.  In this case-control study, two groups of women with and without breast cancer were compared regarding the prevalence of migraine. Each group consisted of 400 women. The diagnosis of different types of headache was made based on The International Headache Society (IHS) guidelines. Type of headache, type and receptor status of breast cancer, as well as history of taking hormonal medications was recorded. Independent t-test and Chi-square tests were used for data analysis.  Relative frequency of migraine headache in the normal woman was 38% compared to 19% in the breast cancer group (P < 0.0001). Tension headache was also significantly more prevalent in the normal group (P < 0.001). The frequency of migraine was significantly lower in estrogen receptor (ER)+/progesterone receptor (PR)− women compared to ER−/PR+ (26 and 43 women, respectively; P = 0.04); however, this difference was not significant for tension headache (P = 0.68).  This study confirmed the lower frequency of migraine, as well as tension headache, in breast cancer sufferers. This could be contributed to several non-hormonal factors, such as a history of long term use of nonsteroidal anti-inflammatory drugs (NSAIDs), and hormonal factors, although only migraine showed a strong link with hormone status.

title: Risk factors for breast cancer according to estrogen and progesterone receptor status.
abstract: Evaluations of epidemiologic risk factors in relation to breast cancer classified jointly by estrogen receptor (ER) and progesterone receptor (PR) status have been inconsistent. To address this issue, we conducted a prospective evaluation of risk factors for breast cancer classified according to receptor status.



During 1 029 414 person-years of follow-up of 66 145 women participating in the Nurses' Health Study from 1980 through 2000, we identified 2096 incident cases of breast cancer for which information on ER/PR status was available: 1281 were ER+/PR+, 318 were ER+/PR-, 80 were ER-/PR+, and 417 were ER-/PR-. We fit a log-incidence model of breast cancer and used polychotomous logistic regression to compare coefficients for breast cancer risk factors in patients with different ER/PR status. To test for differences in risk factor odds ratios based on marginal ER/PR categories, we evaluated ER status controlling for PR status and vice versa. The predictive ability of our log-incidence model to discriminate between women who would develop ER+/PR+ breast cancer and those who would not (and similarly for ER-/PR- breast cancer) was evaluated by using receiver operator characteristic curve analysis. All statistical tests were two-sided.



We observed statistically significant heterogeneity among the four ER/PR categories for some risk factors (age, menopausal status, body mass index [BMI] after menopause, the one-time adverse effect of first pregnancy, and past use of postmenopausal hormones) but not for others (benign breast disease, family history of breast cancer, alcohol use, and height). The one-time adverse association of first pregnancy with incidence was present for PR- but not for PR+ tumors after controlling for ER status (P =.007). However, the association of BMI after menopause with incidence was present for PR+ but not PR- tumors (P =.005). Statistically significant differences in the incidence of ER+ and ER- tumors were seen with age, both before and after menopause (P =.003), and with past use of postmenopausal hormones (P =.01). Area under the receiver operator characteristic curve, adjusted for age, was 0.64 (95% confidence interval [CI] = 0.63 to 0.66) for ER+/PR+ tumors and 0.61 (95% CI = 0.58 to 0.64) for ER-/PR- tumors.



Incidence rates and risk factors for breast cancer differ according to ER and PR status. Thus, to accurately estimate breast cancer risk, breast cancer cases should be divided according to the ER and PR status of the tumor.

title: Course of Migraine During Pregnancy and Postpartum: A Prospective Study
abstract: The aim of this study was to investigate prospectively the course of migraine during pregnancy and postpartum. Of all the pregnant women consecutively attending an obstetrics and gynaecology department for a routine first-trimester antenatal check-up, 49 migraine sufferers - two were affected by migraine with aura (MA) and 47 by migraine without aura (MO) - who had experienced at least one attack during the 3 months preceding pregnancy were identified, enrolled in the study and given a headache diary. Subsequent examinations were performed at the end of the second and third trimesters and 1 month after delivery. Migraine was seen to improve in 46.8% of the 47 MO sufferers during the first trimester, in 83.0% during the second and in 87.2% during the third, while complete remission was attained by 10.6%, 53.2%, and 78.7% of the women, respectively. Migraine recurred during the first week after childbirth in 34.0% of the women and during the first month in 55.3%. Certain risk factors for lack of improvement of migraine during pregnancy were identified: the presence of menstrually related migraine before pregnancy was associated with a lack of headache improvement in the first and third trimesters, while second-trimester hyperemesis, and a pathological pregnancy course were associated with a lack of headache improvement in the second trimester. Breast feeding seemed to protect from migraine recurrence during postpartum.

title: Hormone Withdrawal Symptoms in Oral Contraceptive Users
abstract: To measure the timing, frequency, and severity of hormone-related symptoms in oral contraceptive (OC) users, specifically to compare active-pill with hormone-free intervals.  Using daily diaries, women recorded pelvic pain, bleeding, headaches, analgesic use, nausea or vomiting, bloating or swelling, and breast tenderness during active-pill intervals and hormone-free intervals. Participants either had no prior OC use, had taken OCs and were restarting, or had been taking OCs continuously for 12 months or longer.  Two hundred sixty-two women, 26 with no previous OC use, 43 prior users, and 193 current users, provided daily records of hormone-related symptoms. Subjects with no prior OC use and prior users restarting were similar in no recent OC use, and because of the small sample, they were pooled for analysis as new-start OC users. Current users had patterns of symptoms that were more frequent during hormone-free intervals than during the three active-pill weeks. These included pelvic pain (70% versus 21%, P < .001), headaches (70% versus 53%, P < .001), use of pain medication (69% versus 43%, P < .001), bloating or swelling (58% versus 19%, P < .001), and breast tenderness (38% versus 16%, P < .001). Similar patterns were seen in new-start OC users after the first cycle. Among new-start OC users, menstrual flow patterns, headache, bloating or swelling, and breast-tenderness symptoms decreased during the three cycles to approach those levels of current users.  Almost all symptoms assessed were significantly worse during the 7-day hormone-free interval than during the 21 days of hormone-containing pills.

title: The influence of estrogen on migraine: a systematic review.
abstract: Menstrual migraine affects approximately 50% to 60% of female migraineurs, but knowledge regarding the role of hormones, especially estrogen, appears incomplete.



To conduct a systematic review to determine the role of hormones on menstrual migraine.



MEDLINE (January 1966 through September 1, 2005) and EMBASE Drugs and Pharmacology (January 1991 through September 1, 2005) were searched for articles published in the English language using the keywords migraine, estrogen, menstrual migraine, pure menstrual migraine, true menstrual migraine, menstrually-associated migraine, menstrually-related migraine, pregnancy, breast-feeding, perimenopause, menopause, nitric oxide, and estrogen receptors. A total of 643 unique articles were reviewed for relevance, scientific rigor, and generalizability. For each relevant citation, the bibliography was reviewed to identify additional sources of pertinent data.



The influence of estrogen on migraine is evident by a 3-fold greater prevalence among women compared with men, and by significant changes in migraine incidence with changes in female reproductive status. Menstrual migraines are usually more resistant to treatment, generally not associated with aura, of longer duration, and associated with more functional disability compared with attacks at other times of the month. Biochemical and genetic evidence suggest central and peripheral roles for estrogen in the pathophysiology of menstrual migraine, with potential interactions with excitatory circuits, including serotonergic components. Although evidence for estrogen as a preventive treatment for menstrual migraine is inconsistent, serotonin receptor agonists (triptans) provide acute relief and also may have a role in prevention.



Epidemiological, pathophysiological, and clinical evidence link estrogen to migraine headaches. Triptans appear to provide acute relief and also may be useful for headache prevention. Clear, focused, and evidence-based treatment algorithms are needed to support primary care physicians, neurologists, and gynecologists in the treatment of this common condition.

title: Plasma free serotonin as a marker for early detection of breast cancer recurrence.
abstract: To evaluate the significance of plasma free serotonin (5-hydroxytryptamine) and Ca15.3 for the early detection of breast cancer recurrence.



Free serotonin and Ca15.3 levels were measured by I-125-Serotonin RIA (DDV Diagnostica, Marburg, Germany) in plasma and an ELISA kit (Roche Diagnostic GmbH, Mannheim, Germany) in serum, respectively in women (N=29) who responded to primary treatment for breast cancer and who were followed-up for recurrence. For analysis, patients were sub-divided according to TNM staging into groups with localized (T1-2N0-M0) and advanced (T1-2N1-2M0-1) disease. The control group were healthy blood donors.



Patients with advanced disease had a significantly higher plasma serotonin level than those with localized disease or controls, whereas Ca15.3 levels remained in normal range in all groups. At the time of serotonin measurement, radiological findings were negative for all patients in the localized-disease group, but positive in nine patients in the advanced-disease group.



Plasma free serotonin may be used for the early detection of recurrent/metastatic breast cancer disease, but validation on a larger number of patients is needed.

title: Alcohol Consumption and Breast Cancer Survival: A Meta- analysis of Cohort Studies.
abstract: Evidence for associations between alcohol consumption with breast cancer survival are conflicting, so we conducted the present meta-analysis.



Comprehensive searches were conducted to find cohort studies that evaluated the relationship between alcohol consumption with breast cancer survival. Data were analyzed with meta-analysis software.



We included 25 cohort studies. The meta-analysis results showed that alcohol consumption was not associated with increased breast cancer mortality and recurrence after pooling all data from highest versus lowest comparisons. Subgroup analyses showed that pre-diagnostic or post-diagnostic consumpotion, and ER status did not affect the relationship with breast cancer mortality and recurrence. Although the relationships of different alcohol consumption with breast cancer mortality and recurrence were not significant, there seemed to be a dose-response relationship of alcohol consumption with breast cancer mortality and recurrence. Only alcohol consumption of >20 g/d was associated with increased breast cancer mortality, but not with increased breast cancer recurrence.



Although our meta-analysis showed alcohol drinking was not associated with increased breast cancer mortality and recurrence, there seemed to be a dose-response relationship of alcohol consumption with breast cancer mortality and recurrence and alcohol consumption of >20 g/d was associated with increased breast cancer mortality.

title: Alcohol consumption and breast cancer risk subtypes in the E3N-EPIC cohort
abstract: The aim of this study was to obtain an overview of the associations between alcohol consumption and breast cancer risk at adulthood, by type of alcohol and subtype of breast cancer. Between 1993 and 2008, 66 481 women from the French E3N-EPIC cohort were followed up and asked to report their alcohol consumption, by type of alcohol, through a 208-item diet-history questionnaire. A total of 2812 breast cancer cases were validated during the follow-up session. No association was found between high alcohol consumption, whatever its type, and increase in breast cancer risk in the premenopausal period. During the postmenopausal period, a linear association between total alcohol consumption and breast cancer risk was found (P<0.0001), mainly driven by the associations with wine and beer [hazard ratio=1.33 (1.11–1.58) and 1.85 (1.19–2.89)] for more than two glasses per day of wine and beer, respectively, compared with nondrinkers] and with ER+/PR+ breast cancer subtypes. In the postmenopausal period, we observed interactions between total alcohol and folate intake levels (P=0.1192) and BMI (P=0.0367), with higher increased risks observed for high alcohol intake among women with low folate intake or who were overweight or obese. Our results make precise the current body of knowledge on the relationship between alcohol and breast cancer subtypes. Interactions between alcohol and other factors should further be taken into account in public health nutrition programs.

title: Tobacco smoke exposure and breast cancer risk in Thai urban females.
abstract: The incidence of urban female breast cancer has been continuously increasing over the past decade with unknown etiology. One hypothesis for this increase is carcinogen exposure from tobacco. Therefore, the objective of this study was to investigate the risk of urban female breast cancer from tobacco smoke exposure. The matched case control study was conducted among Thai females, aged 17-76 years and living in Bangkok or its surrounding areas. A total of 444 pairs of cases and controls were recruited from the Thai National Cancer Institute. Cases were newly diagnosed and histologically confirmed as breast cancer while controls were selected from healthy women who visited a patient, matched by age ± 5 years. After obtaining informed consent, tobacco smoke exposure data and information on other potential risk factors were collected by interview. The analysis was performed by conditional logistic regression, and presented with odds ratio (ORs) and 95% confidence intervals(CI). From all subjects, 3.8% of cases and 3.4% of controls were active smokers while 11.0% of cases and 6.1% of controls were passive smokers. The highest to lowest sources of passive tobacco smoke were from spouses (40.8%), the workplace (36.8%) and public areas (26.3%), respectively. After adjusting for other potential risk factors or confounders, females with frequent low-dose passive smoke exposure (≤ 7 hours per week) from a spouse or workplace had adjusted odds ratio 3.77 (95%CI=1.11-12.82) and 4.02 (95%CI=1.04-15.50) higher risk of breast cancer compared with non-smokers, respectively. However, this study did not find any association of breast cancer risk in high dose passive tobacco smoke exposure, or a dose response relationship in cumulative passive tobacco smoke exposure per week, or in the active smoker group. In conclusion, passive smoke exposure may be one important risk factor of urban female breast cancer, particularly, from a spouse or workplace. This risk factor highlights the importance of avoiding tobacco smoke exposure as a key measure for breast cancer prevention and control.

title: Alcohol consumption and hangover patterns among migraine sufferers
abstract: Alcohol hangover is a poorly understood cluster of symptoms occurring following a heavy consumption of alcohol. The term “delayed alcohol-induced headache” is often used synonymously. Our objective was to compare alcohol hangover symptoms in migraine sufferers and nonsufferers.  In this cross-sectional study, university students were asked to fill structured questionnaires assessing headache history, alcoholic consumption, and hangover symptoms (using the Hangover Symptom Scale (HSS)). Subjects were classified as suffering from migraine with or without aura and nonsufferers according the International Classification of Headache Disorders 2nd Edition (ICHD-II). The 13 hangover symptoms were divided by the researches into migraine-like and other nonmigraine-like symptoms.  Hangover symptoms among 95 migraine sufferers and 597 nonsufferers were compared. Migraine sufferers consumed less alcohol compared with the nonsufferers (mean drinks/week 2.34 ± 4.11 vs. 2.92 ± 3.58, P = 0.038) and suffered from higher tendency to migraine-like symptoms after drinking (mean 2.91 ± 3.43 vs. 1.85 ± 2.35, P = 0.002) but not to other hangover symptoms (mean 5.39 ± 6.31 vs. 4.34 ± 4.56, P = 0.1).  Migraine sufferers consume less alcohol, especially beer and liquors, and are more vulnerable to migraine-like hangover symptoms than nonsufferers. The finding that the tendency to develop migraine attacks affects the hangover symptomatology may suggest a similarity in pathophysiology, and possibly in treatment options.

title: Breast cancer and use of nonsteroidal anti-inflammatory drugs: a meta-analysis.
abstract: Breast cancer is one of the leading causes of mortality among women. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with reduced risk for breast cancer, but results from these studies of the association have been inconsistent.



Studies that examined the association between risk of breast cancer and use of NSAIDs, including aspirin and ibuprofen, that were published between January 1, 1966, and July 1, 2008, were identified using Medline, EMBASE, and other databases. We performed meta-analysis by pooling studies according to the inverse of their variances and performed separate analyses of studies pooled according to aspirin use and ibuprofen use. We evaluated publication bias and study quality.



A total of 38 studies (16 case-control studies, 18 cohort studies, 3 case-control studies nested in well-defined cohorts, and 1 clinical trial) that included 2 788 715 subjects were identified. The results of these studies suggest that overall, NSAID use was associated with reduced risk for breast cancer (relative risk [RR] = 0.88, 95% confidence interval [CI] = 0.84 to 0.93). Specific analyses for aspirin (RR = 0.87, 95% CI = 0.82 to 0.92) and ibuprofen (RR = 0.79, 95% CI = 0.64 to 0.97) yielded similar results.



This meta-analysis provides evidence that NSAID use is associated with reduced risk for breast cancer. Future research should include careful evaluation of the biologic mechanisms involved in the relationship between NSAIDs and breast cancer.

title: Use of nonsteroidal anti-inflammatory drugs and reduced breast cancer risk among overweight women
abstract: Chronic inflammation is associated with increased risk of multiple cancers, including breast cancer. Adipose tissues produce proinflammatory cytokines, and obesity is a risk factor for postmenopausal breast cancer. We evaluated the association of regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) with breast cancer risk, overall and by body mass index (BMI) and tumor subtypes defined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status. We conducted a population-based, case-control study involving 5,078 women aged 25-75 years who were recruited primarily from the Nashville metropolitan area of Tennessee. Multivariate unconditional logistic regression models were used to estimate odds ratios and 95 % confidence intervals for breast cancer risk after adjusting for multiple potential confounding factors. Regular use of any NSAID was associated with significantly reduced breast cancer risk (OR 0.78; 95 % CI 0.69–0.89). This association was observed for regular use of baby aspirin only (OR 0.82, 95 % CI 0.69–0.99), other NSAIDs only (OR 0.81, 95 % CI 0.69–0.95), and both baby aspirin and other NSAIDs (OR 0.52, 95 % CI 0.40–0.69). These significant inverse associations were found among overweight women (BMI ≥25 kg/m2) overall and by subtypes of breast cancer, but not among women with BMI <25 kg/m2 (P for interaction = 0.023). Regular use of NSAIDs was inversely associated with breast cancer risk, particularly among overweight women. Overweight women may benefit more from the protective effects of NSAID use than normal-weight women.

title: Migraine in the United States: Epidemiology and patterns of health care use
abstract: ObjectiveTo determine the prevalence and distribution of migraine in the United States as well as current patterns of health care use. MethodsA random-digit-dial, computer-assisted telephone interview (CATI) survey was conducted in Philadelphia County, PA, in 1998. The CATI identifies individuals with migraine (categories 1.1 and 1.2) as defined by the diagnostic criteria of the International Headache Society with high sensitivity (85%) and specificity (96%). Interviews were completed in 4,376 subjects to identify 568 with migraine. Those with 6 or more attacks per year (n = 410) were invited to participate in a follow-up interview about health care utilization and family impact of migraine; 246 (60.0%) participated. ResultsThe 1-year prevalence of migraine was 17.2% in females and 6.0% in males. Prevalence was highest between the ages of 30 and 49. Whereas 48% of migraine sufferers had seen a doctor for headache within the last year (current consulters), 31% had never done so in their lifetimes and 21% had not seen a doctor for headache for at least 1 year (lapsed consulters). Of current or lapsed consulters, 73% reported a physician-made diagnosis of migraine; treatments varied. Of all migraine sufferers, 49% were treated with over-the-counter medications only, 23% with prescription medication only, 23% with both, and 5% with no medications at all. ConclusionRelative to prior cross-sectional surveys, epidemiologic profiles for migraine have remained stable in the United States over the last decade. Self-reported rates of current medical consultation have more than doubled. Moderate increases were seen in the percentage of migraine sufferers who use prescription medications and in the likelihood of receiving a physician diagnosis of migraine.