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The aim of the study was to compare the effects of different hormone therapies on cardiac repolarization in recently postmenopausal women with and without hot flashes.We recruited 150 healthy women: 72 with and 78 without hot flashes. They were randomized and treated for 6 months with transdermal estradiol (1 mg/day), oral estradiol (OE) alone (2 mg/day) or combined with medroxyprogesterone acetate (MPA; 5 mg/day), or placebo. Cardiac repolarization was assessed by measuring QT intervals, rate-dependence of QT-end interval, and T waves from 24-hour electrocardiographic recording before and during hormone therapy, comprising a total of over 20 million QT-interval measurements.Hot flashes were accompanied with shortened median T-peak – T-end interval (at RR interval of 700, 800, and 900 ms; P = 0.040, 0.020, and 0.032; η2 = 0.35, 0.39, and 0.37; respectively) during the use of OE but not transdermal estradiol. In contrast, the addition of MPA to OE lengthened the maximal QT-end (at RR interval of 500 ms, P = 0.016, η2 = 0.27) and the maximal T-peak – T-end interval (at RR interval of 500 and 600 ms; P = 0.016 and 0.032; η2 = 0.25 and 0.22, respectively). These effects were not seen in women without hot flashes.Hot flashes predict beneficial shortening in cardiac repolarization during OE, but not if MPA is combined with OE. These data may provide one explanation for MPA-related cardiac hazards in epidemiological studies.