Sleep Fragmentation and Estradiol Suppression Decrease Fat Oxidation in Premenopausal Women

Abstract

Context: Body fat gain associated with menopause has been attributed to estradiol (E2) withdrawal. Hypoestrogenism is unlikely to be the only contributing factor, however.

Objective: Given the links between sleep and metabolic health, we examined the effects of an experimental menopausal model of sleep fragmentation on energy metabolism.

Methods: Twenty premenopausal women (age 21-45 years) underwent a 5-night inpatient study during the mid-to-late follicular phase (estrogenized; n = 20) and the same protocol was repeated in a subset of the participants (n = 9) following leuprolide-induced E2 suppression (hypo-estrogenized). During each 5-night study, there were 2 nights of unfragmented sleep followed by 3 nights of fragmented sleep. Indirect calorimetry was used to assess fasted resting energy expenditure (REE) and substrate oxidation.

Results: Sleep fragmentation in the estrogenized state increased the respiratory exchange ratio (RER) and carbohydrate oxidation while decreasing fat oxidation (all P < 0.01). Similarly, in the hypo-estrogenized state without sleep fragmentation, RER and carbohydrate oxidation increased and fat oxidation decreased (all P < 0.01); addition of sleep fragmentation to the hypo-estrogenized state did not produce further effects beyond that observed for either intervention alone (P < 0.05). There were no effects of either sleep fragmentation or E2 state on REE.

Conclusion: Sleep fragmentation and hypoestrogenism each independently alter fasting substrate oxidation in a manner that may contribute to body fat gain. These findings are important for understanding mechanisms underlying propensity to body fat gain in women across the menopause transition.

Keywords: estradiol; indirect calorimetry; menopause; sleep fragmentation; substrate oxidation; women.

Figure 1.

Study protocol overview and sleep fragmentation procedure details. A) The study protocol consisted of a 6-day inpatient study with 2 nights of unfragmented (“unfrag”) sleep followed by 3 nights of fragmented (“frag”) sleep. Calorimetry (gray bar) was conducted in the fasted state on day 2 and day 6. B) Sleep was fragmented using an auditory stimulus delivered every 15 minutes that increased in intensity (60-90 dB) until wake was initiated, as indicated by the participant pressing an event marker (EM). C) Once initiated, wake was maintained for 120 seconds using an auditory stimulus and confirmed by an EM every 10 seconds.

Figure 2.

Effects of study interventions: sleep fragmentation and GnRH agonist–induced E2 suppression. A) Polysomnographically recorded sleep stages (non–rapid eye movement stages N1, N2, and N3, and rapid eye movement [REM]), sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), and time-in-bed (TIB) during unfragmented (“unfrag”) and fragmented (“frag”) sleep. B) Box plot showing median, interquartile range, and extreme values for serum E2 concentration in mid/late follicular phase of the menstrual cycle prior to and ~4 weeks post-administration of a GnRH agonist to rapidly suppress E2 levels to the postmenopausal range. Significance is denoted by ** P < 0.01; *** P < 0.001; n.s., nonsignificant (P > 0.05).

Figure 3.

Effect of sleep fragmentation on calorimetry outcomes. Mean ± SEM of A) respiratory exchange ratio (RER), B) resting energy expenditure (REE), C) carbohydrate (CHO) oxidation rate, and D) fat oxidation rate following unfragmented (“unfrag” in solid fill) and fragmented (“frag” in hatched fill) sleep. Significance is denoted by ** P < 0.01.

Figure 4.

Effect of E2 suppression with or without sleep fragmentation on calorimetry outcomes. Mean ± SEM of A) respiratory exchange ratio (RER), B) resting energy expenditure (REE), C) carbohydrate (CHO) oxidation rate, and D) fat oxidation rate following unfragmented (“unfrag”, in solid fill) and fragmented (“frag”, in hatched fill) sleep in an estrogenized (black) and hypo-estrogenized (gray) state. Significance is denoted by * P < 0.05; ** P < 0.01.