Adverse Cardiometabolic Impacts of Sleep Fragmentation and Estradiol Suppression: An Experimental Model of Menopause

Context: Risk of cardiometabolic disease increases in women transitioning to postmenopause, during which estradiol declines universally. Most of these women experience fragmentation of sleep because of nocturnal hot flashes, without a reduction in total sleep time. Objective: 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. Design: 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 2 nights and then experimentally fragmented without reducing total sleep time the next 3 nights. Setting: Inpatient intensive physiological monitoring research facility. Participants: Thirty-eight healthy premenopausal women. Intervention(s): Clinical experimental induced menopause model including GnRH agonist-induced hypoestrogenism and sleep fragmentation. Main outcome measure(s): Leptin and satiety. Results: Estradiol suppression significantly decreased leptin and increased lipid profiles (false discovery rate [FDR]-adjusted P ≤ .05). Sleep fragmentation significantly increased heart rate (FDR-adjusted P = .002) and trended to increase fasting glucose (FDR-adjusted P = .08). Estradiol suppression and sleep fragmentation worsened individual cardiometabolic outcomes by (median, interquartile range) 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. Conclusion: 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.