This K23 will prepare the candidate for a career in clinical and translational migraine research focused on identifying mechanisms involved in migraine triggers by examining both clinical and biological phenotypes and linking them to appropriate treatments. To this end, the proposed training plan and research project will explore the hormonal modulation of migraine among women while simultaneously providing in depth experience in clinical epidemiology and biostatistics as well as in reproductive endocrinology. The training plan includes course work and tutorials involving internationally recognized mentors in each area. The research plan takes advantage of a large and rich data set from an NIH funded longitudinal multi-site study, the Study of Women Across the Nation (SWAN) to assess the influence of sex hormones on headache throughout the menstrual cycle and across the menopausal transition. Migraine is a neurological disorder with significant public health burden. It affects more than 36 million Americans with the annual economic impact in the U.S. estimated to be more than $36 billion (direct medical costs and lost productivity). Migraine is predominantly a disorder of women that has long been linked with sex hormones. However, sex hormones have complex functions that undergo significant changes over the course of women's reproductive lifespan. It has been challenging to study the impact of women's reproductive hormone cycles and the menopause transition on migraine, due to the lack of well characterized daily hormone cycles in women with migraine. Epidemiologic studies show that migraine prevalence increases around the age of menarche, as hormones begin to cycle, and that it declines after menopause. Within menstrual cycles, for the majority of women with migraine, headache attacks are more likely during the two days preceding the onset of bleeding and for the first 3 days of menses. However, although migraine is often attributed to drops in estrogen levels, estrogen withdrawal does not fully explain migraine occurrence across the menstrual cycle. There are limited data regarding the relation of hormonal patterns over the menstrual cycle to migraine, or the relative contributions of estrogen and progesterone. Even less is known regarding the relation of hormone patterns to migraine as women transition through menopause. Furthermore, there is significant heterogeneity in women's vulnerability to hormones, with some women being severely affected by migraines in relation to hormonal fluctuation, while others are minimally or not at all. An ideal way to study the relative contributions of estrogen and progesterone to migraine is to compare ovulatory cycles, where estrogen and progesterone cycle in predictable patterns, with anovulatory cycles where estrogen continues to cycle in the setting of a blunted progesterone profile. No studies have used this approach, and no studies have assessed the relation of hormone cycles to migraine in relation to the stages of the menopause transition. The SWAN study has characterized daily hormone levels as well as daily headache symptom data, and has done so for one menstrual cycle each year for up to 10 years, as these women transitioned from pre- or early perimenopause to postmenopause. The K23 proposal focuses on using 264 women with history of migraine in this unique data set to increase our knowledge of how hormone fluctuations relate to migraine symptoms during the menstrual cycle and across the menopausal transition. Despite the magnitude of public health impact of migraine in women, there is a lack of clinical data regarding hormonal underpinnings of migraine and tremendous heterogeneity regarding the triggering of migraine. Better understanding of the effects of daily hormonal fluctuations on migraine occurrence over the course of menstrual cycle as well as over the menopausal transition can lead to improved parsing- of migraine endophenotypes. This improved awareness will lead to more effective and appropriately timed hormonal treatment of women with migraine.
The proposed project is focused on the complex biological mechanisms that underlie the link between migraine and sex hormones in women. Understanding the influence of hormone levels and change in levels during the menstrual cycle and across menopausal transition on the occurrence and timing of migraine headaches, can help significantly improve the care of women with migraine at the time of the greatest severity of symptoms. The results may lead to the development of more effective treatments for this debilitating condition.
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