Risk of cardiometabolic disease increases in women transitioning to postmenopause, during which estradiol declines universally. Most of these women experience fragmentation of sleep due to nocturnal hot flashes, without a reduction in total sleep time. We examined the independent impact of estradiol suppression, sleep, and their combination on cardiometabolic outcomes categorized as satiety and hunger, lipid profile, cardiac vital signs, and glucoregulation. Participants completed 5-night inpatient studies under eucaloric conditions, once during mid-follicular phase/estrogenized and again under estrogen suppressed conditions, using the same experimental protocol both times. For all participants, sleep was unfragmented the first two nights and then experimentally fragmented without reducing total sleep time the next three nights. Inpatient Intensive Physiological Monitoring research facility. 38 healthy premenopausal women. Clinical experimental induced menopause model including gonadotropin-releasing hormone agonist-induced hypoestrogenism and sleep fragmentation. Leptin and satiety. Estradiol suppression significantly decreased leptin and increased lipid profiles (FDR-adjusted p≤0.05). Sleep fragmentation significantly increased heart rate (FDR-adjusted p=0.002) and trended to increase fasting glucose (FDR-adjusted p=0.08). Estradiol suppression and sleep fragmentation worsened individual cardiometabolic outcomes by (median, IQR) 4.0% (1.5%, 6.3%) from normalized baseline values. Sleep fragmentation worsened a composite cardiometabolic index derived from individual clinical cardiometabolic measures by an additional 103% over estradiol suppression alone. Independent of aging, there are significant adverse changes in cardiometabolic health induced by core components of the transition to postmenopause, including novel effects of sleep fragmentation, a modifiable target.