A double-blind, randomized, placebo-controlled trial of suvorexant for the treatment of vasomotor symptom-associated insomnia disorder in midlife women

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.

Testosterone and depressive symptoms during the late menopause transition

Background The menopause transition is associated with an increased risk of depression. While the mechanisms behind this increased risk are not well understood, the changing perimenopausal hormonal environment has been hypothesized to play a role. The current study examined the potential influence of testosterone and the ratio of testosterone to estradiol as a potential contributor to depressed mood in the menopause transition. Methods Fifty non-depressed perimenopausal women ages 45–55 were recruited for this study. Once every 3 weeks, for a total of four times, the women completed the Centre for Epidemiological Studies-Depression (CES-D) scale for the measurement of depressive symptoms and provided a first-morning urine sample for the measurement of urinary testosterone as well as estrone-3-glucuronide (E1G), a urinary metabolite of estradiol. The week-to-week and mean effects of testosterone, E1G, and the testosterone/E1G ratio on CES-D score were examined. Self-reported sleep quality and vasomotor symptoms were also assessed at each of the four time points. Results Testosterone levels rose with increasing months since last menstrual period associated with testosterone levels (β(SE) = 175.3(63.2), p = .006), though this effect was moderated by body mass index (p for the interaction = .001) such that overweight women showed a less pronounced increase over time. Past and current smokers also had higher testosterone levels compared to never smokers. Week-to-week testosterone/E1G ratio was positively associated with CES-D score (β(SE) = 1.57(0.76), p = .041) but not sleep quality or vasomotor symptoms (ps > .05). Mean testosterone/E1G ratio was also positively associated with vasomotor symptom bother (β(SE) = 0.14(0.06), p = .018) and poorer sleep quality (β(SE) = − 0.34(0.09), p = .0001). Conclusion These results suggest that, within the context of the menopause transition, times that are characterized by a higher testosterone-to-estradiol ratio may be associated with higher depressive symptoms. Perimenopausal women with a higher average ratio of testosterone relative to estradiol may also experience more sleep difficulties and vasomotor symptom bother.

RANKL is a new epigenetic biomarker for the vasomotor symptom during Menopause

During menopausal transition, decreased level of estrogen brings a number of physiological problems and hormonal changes. In this study, promoter methylation of RANKL and FSHR genes were identified in 30 premenopausal and 35 postmenopausal women using methylation-specific high resolution melting (MS-HRM) analysis. The statistical analyses and their association with patient characteristics were performed by Pearson χ2 and Fisher’s exact test (p <0.05). The methylated RANKL gene was detected in 16 postmenopausal cases, and 12 (75.0%) of the RANKL methylated cases had hot flashes (p = 0.024). The methylated FSHR gene was detected in 18 postmenopausal cases, and 13 (75.0%) of the methylated cases had hot flashes (p = 0.028). In vitro studies demonstrated the association between RANKL expression, FSH level and hot flashes in the mouse. Although lack of epigenetic studies in this field proves our results crucial and therefore, our results showed magnitude of epigenetic profiles of Turkish Cypriot post-menopausal women. This was the first study which has investigated the RANKL and FSHR methylation and their relationship with hot flashes in postmenopausal women.