Combined Hormonal Contraceptives: Is It Time to Reassess Their Role in Migraine?

Objective.— This paper will review the extensive array of hormonal contraceptives. It will examine the benefits and risks associated with them – particularly with regard to stroke risk – and shed light on divergent findings in the literature. Background.— Menstrual‐related migraine is a particularly disabling presentation of migraine often deserving of specific prevention. There is accumulating evidence that hormonal preventives may offer such protection. Although a legacy of research shows an increased risk of stroke with high‐dose oral contraceptives (OCs) (those containing 50‐150 µg of estrogen), there is evidence to suggest that this does not apply to ultralow‐dose OCs – those containing <25 µg ethinyl estradiol – when used in appropriate populations (ie, normotensive non‐smokers). Migraine with aura (MwA) increases stroke risk, and that risk is directly correlated to the frequency of aura, a factor that can be modified – either upward or downward – by combined hormonal contraceptives (CHCs). The argument against using CHCs in MwA is based on the concerns that (1) OCs increase stroke risk, (2) MwA increases stroke risk, and (3) combining these risk factors might produce additive or synergistic risk. Evidence does not support concerns (1) and (3), and suggests otherwise. Summary.— The risk/benefit analysis of CHCs is shifting. There is growing evidence for a potential role for CHCs in the prevention of menstrual‐related migraine. At the same time, the risk of these products is declining, as newer and lower dose formulations replace their historical predecessors. And although migraine aura is a risk factor for stroke, there is not convincing evidence to suggest that the addition of a low‐dose CHC alters that risk in non‐smoking, normotensive users. Selected hormonal preventives could potentially decrease stroke risk in MwA via reduction in aura frequency achieved by reducing peak estrogen exposure. With this shift in risk/benefit analysis, it is time to reconsider the role of CHCs in migraine – both with and without aura.     

The Relationship Between Homocysteine and Genes of Folate-Related Enzymes in Migraine Patients

(Headache 2010;50:99‐168) Background.— It has been suggested that homocysteine (Hcy) and the 5′‐10′‐methylenetetrahydrofolate reductase (MTHFR) C677T variant are implicated in the pathogenesis of migraine. Homocysteine has the potential to damage endothelium and accelerate atherosclerosis. Genetic factors such as the MTHFR C677T polymorphism, and other polymorphisms in folate‐related genes associated with high homocysteine levels, may contribute to increasing this vascular risk. Results.— We recruited 427 migraine patients (199 without aura [MO]; 228 with aura [MA]), and 310 controls in a neurologic clinic. Hcy levels and 6 polymorphisms corresponding to 6 folate‐related genes, including the MTHFR C677T variant, were determined in all migraine participants and in a subset of 155 controls. We found higher sex‐adjusted Hcy levels in MA (mean: 11.02 µM) than MO patients (9.86 µM; P = .005 for the difference). Hcy levels higher than 12.0 µM doubled the risk for MA (OR = 2.145; 95% confidence intervals [CI] = 1.3‐3.4; P = .001), and those higher than 15.0 µM incurred a 6‐fold increase (OR = 5.95; 95% CI = 2.1‐20.0, P < .001). The number of MTHFR 677T alleles was the best genetic predictor of Hcy levels (r² = 0.06; P = 6.2e‐6; corrected for genetic variants analyzed) and this effect remained significant after correction for other confounding factors. Using multi‐dimensionality reduction approaches, we observed significant epigenetic interaction among some of the folate‐related genetic variants to predict higher Hcy levels, and also among higher Hcy levels and folate‐related genetic variants to predict the end‐diagnosis of MA only among migraineurs. In controls, Hcy levels and the number of MTHFR 677T alleles were found to be intermediate between those observed in MA and MO patients. Conclusion.— Our results suggest that MA patients have higher Hcy levels. We also observed complex epigenetic interaction among folate‐related enzymes, sex, and Hcy levels predicting MA phenotype. Nevertheless, genetic factors explained only a minor proportion of the variance for both Hcy plasma levels and for predicting MA phenotype. Determination of MTHFR C677T polymorphisms and Hcy levels may be useful to identify patients with a high risk of suffering from MA.     

Sporadic hemiplegic migraine is an aetiologically heterogeneous disorder

In order to better understand sporadic hemiplegic migraine (SHM) and particularly its relation to familial hemiplegic migraine (FHM), migraine without aura (MO) and typical migraine with aura (typical MA), we investigated the occurrence of MO and typical MA among probands with SHM and their first-degree relatives. The pattern of familial aggregation of MO and typical MA was assessed by population relative risk calculations. A total of 105 SHM probands and 483 first-degree relatives were identified in the Danish population. Compared with the general population, SHM probands had no increased risk of MO, but a highly increased risk of typical MA. First-degree relatives of all SHM probands had an increased risk of both MO and typical MA, whereas first-degree relatives of probands with exclusively SHM had no increased risk of MO but an increased risk of typical MA. Our data suggest that SHM is a genetically heterogeneous disorder.     

MicroRNA expression profiles analysis of apheresis platelets treated with vitamin B2 and ultraviolet-B during storage

Whether platelet (PLT) microRNA (miRNA) profiles are affected by pathogen reduction technology (PRT) using vitamin B₂ and ultraviolet-B (VB₂-PRT) remains unclear. Samples from VB₂-PRT-treated (experimental group, E_) and untreated (control group, C_) apheresis PLTs were taken on days 1, 3 and 5 of storage, designated as E_1, E_3, E_5, C_1, C_3 and C_5, respectively. The miRNA expression profiles were assessed by DNA Nano Ball (DNB) sequencing technology, and verified by quantitive real-time fluorescence quantitative PCR (qRT-PCR). Compared with the expression profiles of PLT miRNAs, 3895 miRNAs were identified in the E_ groups while 4106 were in the C_ groups. There were 487 significant differentially expressed miRNAs in E_1 vs C_1 group, including 220 upregulated and 287 downregulated, such as miR-146a-5p and let-7b-5p. There were 908 significant differentially expressed miRNAs in E_3 vs C_3 group, including 297 upregulated and 611 downregulated, such as miR-142-5p and miR-7-5p. There were 229 significant differentially expressed miRNAs in E_5 vs C_5 group, including 80 upregulated and 149 downregulated, such as miR-3529-3p and miR-451a. These differentially expressed miRNAs had been suggested to have functional roles in energy homeostasis, cell communication, proliferation, migration and apoptosis. GO analysis showed a significant enrichmen in relevant biological process categories as receptor activity, signal transduction, cell transport, motility and chemotaxis. The significantly enriched KEGG pathway of predicted target genes was Glycosaminoglycan biosynthesis in E_ vs C_ groups. These new observation could provide insights on the understanding of change of miRNA profiles of PLT treated with VB₂-PRT.     

The impact of extended-cycle vaginal ring contraception on migraine aura: a retrospective case series

Objective.— To determine whether extended‐cycle dosing of an ultralow dose vaginal ring contraceptive decreases frequency of migraine aura and prevents menstrual related migraine (MRM). Background.— Many women are denied therapy with combined hormonal contraceptives due to published guidelines that recommend against their use in migraine with aura (MwA). The concern is that these products might further elevate the risk of ischemic stroke that accompanies aura. Stroke risk has been reported to vary directly with aura frequency, and aura frequency in turn has been shown to have a direct relationship to estrogen concentration. With the evolution of increasingly lower dosed combined hormonal contraceptives, we now have formulations that – provided that ovulation is inhibited – result in lower peak levels of estrogen than the concentrations attained during the native menstrual cycle. These formulations would thus be expected to result in a lower frequency of migraine aura. Furthermore, as extended‐cycle therapy eliminates monthly estrogen withdrawals, this therapy would likewise be expected to prevent MRM. Methods.— This pilot study is an institutional review board‐approved retrospective database review. We queried our database of 830 women seen in a subspecialty menstrual migraine clinic to identify women who met all inclusion criteria: (1) current history of MwA; (2) confirmed diagnosis of MRM; and (3) treatment with extended‐cycle dosing of a transvaginal ring contraceptive containing 0.120 mg etonogestrel/15 µg ethinyl estradiol. Standardized calendars that specifically document bleeding patterns, headache details, and occurrence of aura are required of all patients in this clinic. Results.— Twenty‐eight women met study criteria, none of whom were smokers. Of these, 5 discontinued use of etonogestrel/ethinyl estradiol within the first month, leaving 23 evaluable subjects. At baseline, subjects averaged 3.23 migraine auras/month (range: 0.1‐12). With extended dosing of the vaginal ring contraceptive, median frequency was reduced to 0.23 auras per month following treatment after a mean observation of 7.8 months (P < .0005). No subject reported an increase in aura frequency. On this regimen, MRM was eliminated in 91.3% of the evaluable subjects. Conclusion.— In this sample of women with both MwA and MRM, use of an extended‐cycle vaginal ring contraceptive was associated with a reduced frequency of migraine aura and with resolution of MRM. This cannot be extrapolated to suggest that stroke risk in MwA will be similarly reduced. Studies to evaluate this relationship are warranted.     

Reversible Hemiparesis in a Patient With Migraine

ABSTRACT

A third of patients with migraine may experience accompanying aura, and when this includes motor weakness, the condition is described as hemiplegic migraine. Young women who suffer from migraine with aura have a 6.2-fold increased risk of ischemic stroke. The slow progression and succession of symptoms help to provide the diagnosis of hemiplegic migraine.

This report is adapted from paineurope 2014; Issue 1, ©Haymarket Medical Publications Ltd., and is presented with permission. paineurope is provided as a service to pain management by Mundipharma International, Ltd., and is distributed free of charge to health care professionals in Europe. Archival issues can be accessed via the Web site: http://www.paineurope.com at which European health professionals can register online to receive copies of the quarterly publication.     

Calcitonin gene-related peptide does not cause migraine attacks in patients with familial hemiplegic migraine

(Headache 2011;51:544‐553) Background.— Calcitonin gene‐related peptide (CGRP) is a key molecule in migraine pathogenesis. Intravenous CGRP triggers migraine‐like attacks in patients with migraine with aura and without aura. In contrast, patients with familial hemiplegic migraine (FHM) with known mutations did not report more migraine‐like attacks compared to controls. Whether CGRP triggers migraine‐like attacks in FHM patients without known mutations is unknown. Objective.— In the present study we therefore examined the migraine‐inducing effect of CGRP in FHM patients without known mutations and healthy controls. Methods and design.— Eleven patients suffering from FHM without known mutations and 11 controls received an intravenous infusion of 1.5 µg/minute CGRP over 20 minutes. The study design was a balanced and controlled provocation study. Headache and other migraine symptoms were scored for 1 hour and self‐recorded hourly thereafter until 13‐hour postinfusion. Results.— We found no difference in the incidence of migraine‐like attacks between the 2 groups, with 9% (1 of 11) of patients and 0% (0 of 10) of controls reporting migraine‐like headache (P = 1.00). CGRP infusion did not induce aura symptoms in any of the participants. There was no difference in the incidence of CGRP‐induced delayed headaches between the groups (P = .18). Conclusion.— In contrast to patients suffering from migraine with aura and without aura, CGRP infusion did not induce more migraine‐like attacks in FHM patients without known mutations compared to controls. It seems that the majority of FHM patients with and without known mutation display no sensitivity to CGRP signaling compared to common types of migraine.     

Sporadic hemiplegic migraine

Sporadic hemiplegic migraine (SHM) is defined as migraine attacks associated with some degree of motor weakness/hemiparesis during the aura phase and where no first degree relative (parent, sibling or child) has identical attacks. The present review deals with recent scientific studies according to which: The SHM prevalence is estimated to be 0.005%; SHM patients have clinical symptoms identical to patients with familial hemiplegic migraine (FHM) and significantly different from patients with migraine with typical aura (typical MA); SHM affected had no increased risk of migraine without aura (MO), but a highly increased risk of typical MA compared to the general population; SHM patients only rarely have mutations in the FHM gene CACNA1A; SHM attacks in some cases can be treated with Verapamil. The reviewed data underlie the change in the International Classification of Headache Disorders 2nd edition where SHM became separated from migraine with typical aura or migraine with prolonged aura. All cases with motor weakness should be classified as either FHM or SHM.     

Migraine without aura and migraine with aura are inherited disorders

The familial occurrence and mode of inheritance were analysed in families with migraine without aura (MO) and migraine with aura (MA). The probands were found among 4000 persons from the general population. All persons with MA were included as probands, and an equivalent number of probands with MO was selected as a random sample among those with MO. Spouses and first-degree relatives were blindly interviewed. All interviews were performed by one neurological research fellow. The distinct familial patterns indicate that MO and MA have a different aetiology. Compared with the general population, the first-degree relatives of probands with MO had a 1.9-fold increased risk of MO while spouses had a 1.5-fold increased risk of MO, indicating that both genetic and environmental factors are important in MO. The first-degree relatives of probands with MA had a four-fold increased risk of MA while spouses had no increased risk of MA, indicating that MA is determined largely by genetic factors. The complex segregation analysis indicate that both MO and MA have multifactorial inheritance without generational difference.     

Migraine,Migraine Features,and Cardiovascular Disease

(Headache 2010;50:1031‐1040) Background.— Many studies support an association between migraine and cardiovascular disease (CVD). This association appears particularly in migraine with aura and is also modified by additional factors. Objective.— We sought to investigate whether the association between migraine and CVD in addition to aura status is affected by certain migraine features. Methods.— Cohort study among 27,840 women, participating in the Women's Health Study. We had detailed self‐reported information on migraine and migraine features among women with active migraine (migraine during the year prior to baseline). Incident CVD events were confirmed after medical record review. We used Cox proportional hazards models to evaluate the association between migraine and incident CVD. The results have been presented in part before. We ran additional analyses according to migraine features. Results.— At baseline, 5125 (18.4%) women reported history of migraine; 39.7% of the 3610 women with active migraine indicated aura. During a mean of 11.9 years of follow‐up, 708 CVD events occurred. Migraine with aura doubled the risk for CVD, ischemic stroke, and myocardial infarction. With regard to ischemic stroke, this association seemed stronger in the absence than in the presence of migraine features. This was most pronounced in the absence (hazard ratio = 3.27; 95% CI = 1.93‐5.51; P < .0001) than in the presence of nausea/vomiting (hazard ratio = 0.91; 95% CI = 0.43‐1.93; P = .80). In contrast, the association with myocardial infarction did not reveal a certain pattern. Conclusions.— These data suggest that the association between migraine with aura and ischemic stroke may differ by absence or presence of migraine features.     

Prevalence of migraine in Noonan syndrome

A randomized double-controlled trial involving 22 patients with Noonan syndrome (NS) and 22 normal individuals (control group) was carried out to determine the prevalence of migraine in patients with NS. The NS group consisted of 11 males aged 19.55 +/- 6.11 years and 11 females aged 18.81 +/- 5.47 years. The control group consisted of 11 males aged 19.55 +/- 6.6 years and 11 females aged 18.81 +/- 5.47 years. Seven NS-group patients reported migraine without aura (MO), and three reported probable MO (PMO). Taken together, these represent a prevalence of migraine in the NS group of 45.5%. Two control-group patients reported MO, a prevalence of 9.09%. The prevalence of migraine was significantly higher in the NS-group patients than in the controls (P < 0.005), suggesting a positive association between NS and migraine. Nevertheless, further studies are needed to confirm our findings.     

<Emphasis Type="Italic">Helicobacter pylori</Emphasis> infection as an environmental risk factor for migraine without aura

Helicobacter pylori (H. pylori) infection has recently been associated with various extraintestinal pathologies and migraine. The aim of this study was to investigate the correlation of the H. pylori infection with the pathogenesis of migraine without aura, especially in cases not affected by endogenous risk factors, like hereditary pattern or hormonal fluctuations. A total of 49 outpatients (37 females and 12 males; age range: 19–47 years; mean age: 31,±14 years) affected by migraine without aura was evaluated. We divided them in 2 subgroups: a) with positive familial history, and/or with menstrual type of migraine b) with negative familial history and with menstrual unrelated type of migraine. H. pylori infection was diagnosed by the 13 C- urea breath test (INFAI — test). Control subjects consisted of 51 patients without any primary headache history (38 females; mean age of 32,±14,4 years; range 21–49 years), who underwent upper gastrointestinal (GI) endoscopy for investigation of anaemia or non ulcer dyspepsia. H. pylori detection was based on the histologic analysis of gastric mucosa biopsy. The prevalence of H. pylori infection was significantly higher in the migraineurs without aura compared to controls (p=0.016). The prevalence of H. pylori infection was significantly high in the mixed and in the female group of our patients without other predisposing factors for migraine without aura (81 and 87% respectively), while in the same groups with predisposing factors (menstruation and/or family history) the prevalence was only 36 and 37% respectively (p=0,001 for the first group and p=0,002 for the second group). Our results seem to highlight the role of H. pylori infection as a probable independent environmental risk factor for migraine without aura, especially in patients that are not genetically or hormonally susceptible to migraine.     

Interrelation of chronic tension-type headache with and without medication overuse and migraine in the general population: the Akershus study of chronic headache

We studied the interrelation of chronic tension-type headache with and without medication overuse (CTTH) and migraine in a random sample of 30 000 persons aged 30–44 years. They received a mailed questionnaire. Those with a possible chronic headache were interviewed by neurological residents. The International Classification of Headache Disorders was used. A total of 386 persons had CTTH. Compared with the general population, men had a 2.8-fold and women a 2.4-fold significantly increased risk of migraine without aura (MO). The risk of migraine with aura (MA) was not increased. The mean age at onset of CTTH was significantly higher in those with than in those without co-occurrence of MO. Bilateral MO attacks were significantly more frequent in those with age at onset of CTTH prior to age at onset of MO compared with those with age at onset in reverse order. CTTH and MO are interrelated, possibly in a complex matter. In contrast, CTTH and MA are not interrelated.     

系统性硬化症患者血浆7种miRNA水平与脏器累及和临床指标的相关性

目的 检测系统性硬化症患者血浆microRNA(miRNA)的相对表达量,分析其与患者临床指标的相关性.方法 选取49例系统性硬化症患者和同期体检健康者20例,采集静脉血,用实时荧光定量PCR(qRT?PCR)检测血浆中7种miRNA(miR?140?5p、miR?21、miR?142?3p、miR?29a、miR?9...     

K562细胞及其耐药细胞株K562/A02细胞白血病耐药相关microRNA筛选

目的 通过检测慢性粒细胞白血病急变细胞系K562及其阿霉素耐药株K562/A02的微小RNA(microRNA、miR)表达差异,探讨microRNA与白血病化疗耐药的关系.方法 MTT法检测K562/A02及其亲本细胞系K562的耐药性能;流式细胞术检测K562与K562/A02细胞的P-gp表达;运用microRNA芯片技术筛查K562与K562/A02细胞之间差异表达的microRNA,随后用实时荧光定量RT-PCR方法进一步证实.结果 阿霉素耐药株K562/A02相对于其亲本细胞系K562对阿霉素的耐药倍数为180倍;K562细胞P-gp的表达率为0.2%,K562/A02细胞P-gp的表达率为86%;microRNA芯片结果显示K562/A02与K562细胞之间有22种microRNA表达存在显著的差异(P<0.01),表达差异在2倍以上的有9种,其中miR-221、miR-155、miR-451在K562/A02细胞表达上调,而miR-98、miR-181a、let-7f、miR-424、let-7g和miR-563则表达下调.实时荧光定量RT-PCR进一步证实了上述结果,并显示miR-451、miR-155、miR-221、let-7f、miR-424在两种细胞中表达差异显著.结论 K562/A02与K562细胞存在microRNA表达差异,其中miR-451、miR-155和miR-221在K562/A02中表达显著上调,而let-7f、miR-424则显著下调,提示microRNA可能参与白血病耐药形成,差异表达的microRNA可能为逆转白血病耐药提供新的作用靶点.     

Migraine with aura and reproductive life events: a case control study

The course of migraine without aura (MO) is greatly influenced by the events of female reproductive life. Much less is known about migraine with aura (MA). The aim of this study was to evaluate the relationship between MA and the milestones of reproductive life. A retrospective case control study was carried out on 100 women affected by migraine with typical aura (cases) and 200 age-matched women with MO (controls). Premenstrual syndrome was found to be much more common among the patients with MA (odds ratio (OR) 6.0; confidence interval (CI) 3.1-11.6). Menstrually triggered migraine was more frequently encountered among MO than among MA patients (MA 15.0%; MO 53.5%; OR 0.1; CI 0.1-0.3). In both forms of migraine, pregnancy had a favourable effect; however, a lower percentage of MA (43.6%) than MO patients (76.8%; OR 0.2; CI 0.1-0.5) showed improvement or remission. The use of oral contraceptives worsened migraine in MA more frequently than in MO patients (MA 56.4%; MO 25.3%; OR 3.8; CI 1.6-9.3). The course of MA seems to be influenced by female reproductive life events, but in a different way with respect to MO.     

K562细胞及其耐药细胞株K562/A02细胞白血病耐药相关microRNA筛选

目的 通过检测慢性粒细胞白血病急变细胞系K562及其阿霉素耐药株K562/A02的微小RNA(microRNA、miR)表达差异,探讨microRNA与白血病化疗耐药的关系.方法 MTT法检测K562/A02及其亲本细胞系K562的耐药性能;流式细胞术检测K562与K562/A02细胞的P-gp表达;运用microRNA芯片技术筛查K562与K562/A02细胞之间差异表达的microRNA,随后用实时荧光定量RT-PCR方法进一步证实.结果 阿霉素耐药株K562/A02相对于其亲本细胞系K562对阿霉素的耐药倍数为180倍;K562细胞P-gp的表达率为0.2%,K562/A02细胞P-gp的表达率为86%;microRNA芯片结果显示K562/A02与K562细胞之间有22种microRNA表达存在显著的差异(P<0.01),表达差异在2倍以上的有9种,其中miR-221、miR-155、miR-451在K562/A02细胞表达上调,而miR-98、miR-181a、let-7f、miR-424、let-7g和miR-563则表达下调.实时荧光定量RT-PCR进一步证实了上述结果,并显示miR-451、miR-155、miR-221、let-7f、miR-424在两种细胞中表达差异显著.结论 K562/A02与K562细胞存在microRNA表达差异,其中miR-451、miR-155和miR-221在K562/A02中表达显著上调,而let-7f、miR-424则显著下调,提示microRNA可能参与白血病耐药形成,差异表达的microRNA可能为逆转白血病耐药提供新的作用靶点.     

MTHFR 677C>T and ACE D/I Polymorphisms in Migraine: A Systematic Review and Meta‐Analysis

(Headache 2010;50:588‐599) Background.— Data on the association between the MTHFR 677C>T and ACE D/I polymorphisms and migraine including aura status are conflicting. Objective.— The objective of this study is to perform a systematic review and meta‐analysis on this topic. Methods.— We searched for studies published until March 2009 using electronic databases (MEDLINE, EMBASE, Science Citation Index) and reference lists of studies and reviews on the topic. Assessment for eligibility of studies and extraction of data was performed by 2 independent investigators. For each study we calculated the odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs. Results.— Thirteen studies investigated the association between the MTHFR 677C>T polymorphism and migraine. The TT genotype was associated with an increased risk for any migraine, which only appeared for migraine with aura (pooled OR = 1.48, 95% CI 1.02‐2.13), but not for migraine without aura. Nine studies investigated the association of the ACE D/I polymorphism with migraine. The II genotype was associated with a reduced risk for migraine with aura (pooled OR = 0.71, 95% CI 0.55‐0.93) and migraine without aura (pooled OR = 0.84, 95% CI 0.70‐0.99). Results for both variants were driven by studies in non‐Caucasian populations. Results among Caucasians did not suggest an association. Extractable data did not allow investigation of gene–gene interactions. Conslusions.— The MTHFR 677TT genotype is associated with an increased risk for migraine with aura, while the ACE II genotype is protective against both migraine with and without aura. Results for both variants appeared only among non‐Caucasian populations. There was no association among Caucasians.     

Hormonal Contraceptives and Migraine With Aura—Is There Still a Risk?

Unnecessary confusion still surrounds the use of combined hormonal contraceptives (CHCs) in the setting of migraine with aura (MwA). Clearing this confusion is a key issue for headache specialists, since most women with migraine have menstrual‐related migraine (MRM), and some CHCs can prevent this particularly severe migraine. Their use, however, is still restricted by current guidelines due to concerns of increased stroke risk – concerns that originated over half a century ago in the era of high dose contraceptives. Yet studies consistently show that stroke risk is not increased with today's very low dose CHCs containing 20‐25 µg ethinyl estradiol (EE), and continuous ultra low‐dose formulations (10‐15 µg EE) may even reduce aura frequency, thereby potentially decreasing stroke risk. This article clarifies the stroke risk of CHCs and examines their impact on migraine. It also examines how stroke risk is altered by the estrogen content of the CHC, by contributing factors such as smoking, age and hypertension, and by aura frequency. And finally, it puts these risks into a meaningful context with a risk/benefit assessment.