Objective-Sex hormones may be critical determinants of ischemic heart disease and death in women, but results from previous studies are conflicting.To clarify this, we tested the hypothesis that extreme plasma concentrations of endogenous estradiol and testosterone are associated with risk of ischemic heart disease and death in women. Approach and Results-In a nested prospective cohort study, we measured plasma estradiol in 4600 and total testosterone in 4716 women not receiving oral contraceptives or hormonal replacement therapy from the 1981 to 1983 examination of the Copenhagen City Heart Study. During ≤30 years of follow-up, 1013 women developed ischemic heart disease and 2716 died. In women with a plasma estradiol below the fifth percentile compared with between the 10th and 89th percentiles, multifactorially adjusted risk of ischemic heart disease was 44% (95% confidence interval, 14%-81%) higher; however, plasma estradiol concentrations did not associate with death. Also, in women with a plasma testosterone concentration at or above the 95th percentile compared with between the 10th and 89th percentiles, multifactorially adjusted risk was 68% (34%-210%) higher for ischemic heart disease, 36% (18%-58%) higher for any death, and 38% (15%-65%) higher for death from other causes than cardiovascular disease and cancer. These results were similar for postmenopausal women alone. Conclusions-In women, extreme low concentrations of endogenous estradiol were associated with high risk of ischemic heart disease, and extreme high concentrations of endogenous testosterone were associated with high risk of ischemic heart disease and death. compared with younger women, percentiles of sex hormones were generated in 10-year age groups. Materials and MethodsMaterials and methods are available in the online-only Data Supplement. ResultsIn this nested cohort study, we included 4716 women from the 1981 to 1983 examination of the Copenhagen City Heart Study, which in total examined 12 698 individuals (7018 women and 5680 men) and is a prospective general population study, initiated in 1976 to 1978 with follow-up examinations in 1981 to 1983, 1991 to 1994, and 2001 to 2003. Among the 7018 women, plasma was available on 6023; however, as 247 women receiving oral contraceptives and 1060 receiving hormonal replacement therapy at baseline were excluded, plasma estradiol and testosterone measurements were available in 4600 and 4716 women for the present study. Baseline characteristics of these women are shown in the Table. Plasma Estradiol and TestosteroneFor plasma estradiol and testosterone concentrations, the median value was 445 pmol/L (interquartile range, 280-760; 95% confidence interval, 160-2170) in premenopausal and 150 pmol/L (120-180; 60-240) in postmenopausal women (Figure 1). For plasma testosterone concentrations, the corresponding values were 1.9 nmol/L (1.6-2.3; 1.1-3.1) in premenopausal and 1.9 nmol/L (1.5-2.3; 1.1-3.1) in postmenopausal women. Plasma estradiol and testosterone concentrations were relatively high in ...