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Study Objectives The neuropeptide orexin promotes wakefulness, modulates thermoregulation, increases after menopause, and is normalized in women receiving estrogen therapy, suggesting a role for orexin antagonism as a treatment for vasomotor symptom (VMS)-associated insomnia disorder. We tested the efficacy of the dual orexin receptor antagonist suvorexant for chronic insomnia related to nighttime VMS. Methods In a double-blind, placebo-controlled trial, 56 women with chronic insomnia associated with nighttime VMS, Insomnia Severity Index (ISI) scores ≥15, and >30 minutes of diary-rated wake after sleep-onset (WASO) were randomized to receive oral suvorexant 10-20 mg (n=27) or placebo (n=29) nightly for 4 weeks. Analysis of within-person change in ISI was adjusted for baseline ISI and race. Results Mean baseline ISI scores were 18.1 (95% CI, 16.8-19.4) and 18.3 (95% CI, 17.2-19.5) in the suvorexant and placebo groups, respectively (p=0.81). The average 4-week ISI within-person decrease from baseline was greater on suvorexant [-8.1 (95% CI, -10.2 to -6.0)] compared to placebo [-5.6 (95% CI, -7.4 to -3.9), p=0.04]. Compared to placebo, nighttime diary-rated VMS frequency was significantly reduced with suvorexant (p<0.01). While diary-rated WASO and total sleep time trended toward improvement on suvorexant, findings were not significant after adjustment for multiple comparison. Daytime VMS and other sleep-related outcomes did not differ between groups. Suvorexant was well tolerated. Conclusion These results suggest that suvorexant is likely a well-tolerated and efficacious treatment for VMS-associated insomnia disorder and reduces nighttime VMS. Antagonism of orexin receptors could provide a novel therapeutic option for midlife women with VMS-associated chronic insomnia.

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. Design Premenopausal women were studied in two 5-night inpatient studies during the mid-to-late follicular phase (estrogenized; n=20) and repeated in a subset (n=9) following leuprolide-induced E2 suppression (hypo-estrogenized). During each 5-night study, there were two nights of unfragmented sleep followed by three nights of fragmented sleep. Setting Academic medical center. Participants Twenty premenopausal women (age 21-45 years) Interventions Sleep fragmentation and estradiol suppression. Main outcome measures 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. Conclusions 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.