Response to Letter by Tsuda
We appreciate Dr Tsuda’s interest in our findings1 and the query regarding the possible importance of menstrual cycle-related endogenous estrogen status on endothelial biomarker levels in this population of premenopausal migraineurs. For many years, ovarian hormones have been of great interest in the study of migraine pathophysiology because in addition to the effects on the vasculature, there are modulating effects on neuronal excitability, on synthesis and release of nitric oxide and neuropeptides as well as on serotonergic, adrenergic, and γ-aminobutyric acidergic systems.2 Dr Tsuda thoughtfully recounts several studies demonstrating the influence of estrogen (and progesterone) on vascular function, including one describing modulation of endothelial reactivity and smooth muscle sensitivity to nitric oxide in response to the changing hormonal patterns of the menstrual cycle.3 To our understanding, the presence and nature of the variation of endothelial activation biomarkers across the menstrual cycle have been less well delineated. Some small studies of von Willebrand factor, for instance, showed no variation across the menstrual cycle, whereas others showed a decrease during menstruation.4 The sum of studies on the effects ovarian hormones on C-reactive protein demonstrate differences based on whether the hormones are endogenous or exogenous in addition to an inverse relationship of estrogen and progesterone on C-reactive protein.5 In our study, we controlled for use of hormonal contraception, but we agree with Dr Tsuda that ovarian hormone effects may play an important role, and future studies should control for phase of the menstrual cycle as well for ovarian hormone levels.
Sources of Funding
This study was conducted with funding from GlaxoSmithKline and a University of Toledo Translational Research Stimulation Award.