Publications

INTRODUCTION: Most women develop MS before menopause. Menopausal hot flashes can worsen MS symptoms, and could be relieved with hormone therapy. Our objective was to evaluate feasibility, tolerability and symptom response of Duavee® (bazedoxifene + conjugated estrogen) in a Phase Ib/IIa double-blind randomized controlled clinical trial.

METHODS: We randomized 24 peri/postmenopausal women with MS and symptomatic hot flashes 1:1 to Duavee® versus placebo. Evaluations occurred at baseline and 2 months.

RESULTS: Groups were balanced for age (mean 51.2 ± 3.6 years), EDSS [median 3 (IQR:2.5, 4.5)], and MS duration. 21/24 participants completed the study.

FEASIBILITY: Enrollment was protracted (34 months), partially due to concerns about hormone therapy safety.

TOLERABILITY: treatment group participants reported greater satisfaction and fewer missed doses; one participant (placebo) developed new MRI lesions; liver function testing remained normal for all patients.

SYMPTOMS: Hot Flash Related Daily Interference scale at 2 months was lower in treatment vs. placebo group [median (IQR) of 4 (0.5, 14) vs. 9 (0, 33)]. Between-group differences were not statistically significant.

CONCLUSION: Despite perceived benefits in MS, estrogens have perceived risks that represent a hurdle to enrollment. With appropriate education and screening of participants, the favorable study retention (87%) and treatment satisfaction observed in the current study support the feasibility of a longer, powered trial to evaluate whether a proven treatment for menopausal symptoms, Duavee®, could also improve MS-related function in menopausal women with MS.

Circadian adaptation to shifted sleep/wake schedules may be facilitated by optimizing the timing, intensity and spectral characteristics of light exposure, which is the principal time cue for mammalian circadian pacemaker, and possibly by strategically timing nonphotic time cues such as exercise. Therefore, circadian phase resetting by light and exercise was assessed in 44 healthy participants (22 females, mean age [±SD] 36.2 ± 9.2 years), who completed 8-day inpatient experiments simulating night shiftwork, which included either an 8 h advance or 8 h delay in sleep/wake schedules. In the advance protocol (n = 18), schedules were shifted either gradually (1.6 h/day across 5 days) or abruptly (slam shift, 8 h in 1 day and maintained across 5 days). Both advance protocols included a dynamic lighting schedule (DLS) with 6.5 h exposure of blue-enriched white light (704 melanopic equivalent daylight illuminance [melEDI] lux) during the day and dimmer blue-depleted light (26 melEDI lux) for 2 h immediately before sleep on the shifted schedule. In the delay protocol (n = 26), schedules were only abruptly delayed but included four different lighting conditions: (1) 8 h continuous room-light control; (2) 8 h continuous blue-enriched light; (3) intermittent (7 × 15 min pulses/8 h) blue-enriched light; (4) 8 h continuous blue-enriched light plus moderate intensity exercise. In the room-light control, participants received dimmer white light for 30 min before bedtime, whereas in the other three delay protocols participants received dimmer blue-depleted light for 30 min before bedtime. Both the slam and gradual advance protocols induced similar shifts in circadian phase (3.28 h ± 0.37 vs. 2.88 h ± 0.31, respectively, p = .43) estimated by the change in the timing of timing of dim light melatonin onset. In the delay protocol, the continuous 8 h blue-enriched exposure induced significantly larger shifts than the room light control (-6.59 h ± 0.43 vs. -4.74 h ± 0.62, respectively, p = .02). The intermittent exposure induced  60% of the shift (-3.90 h ± 0.62) compared with 8 h blue-enriched continuous light with only 25% of the exposure duration. The addition of exercise to the 8 h continuous blue-enriched light did not result in significantly larger phase shifts (-6.59 h ± 0.43 vs. -6.41 h ± 0.69, p = .80). Collectively, our results demonstrate that, when attempting to adapt to an 8 h overnight work shift, delay shifts are more successful, particularly when accompanied by a DLS with high-melanopic irradiance light stimulus during wake.

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.

LEARNING OBJECTIVES: After participating in this activity, learners should be better able to:• Outline the clinical recommendations for menopausal hormone treatment related to cognitive concerns• Debate and discuss the various research pieces on the use of menopausal hormone therapy cognitive decline, dysfunction, and dementia.

ABSTRACT: Menopause has been associated with subjective cognitive dysfunction and elevated rates of depression. While menopausal hormone therapy (MHT) is Food and Drug Administration-approved for the treatment of vasomotor symptoms related to menopause, a potential role for MHT in treating and preventing cognitive decline, dysfunction, and dementia has remained unclear and a topic of continued interest and debate across decades of research. Increasing numbers of patients are seeking help for subjective cognitive decline, and those with poorer mental health are substantially more likely to perceive themselves to be at high risk of developing dementia; thus, mental health professionals are likely to encounter such patients and may be asked to provide advice concerning MHT, cognition, and indications for MHT use. Here, we synthesize the neurobiological effects of MHT, make recommendations for its use in current clinical practice in the contexts of cognitive dysfunction associated with major depressive disorder, cognitive decline, and Alzheimer's disease, and discuss the frontiers being explored by ongoing research on this topic. We conclude that MHT to improve cognitive functioning has only a few scenarios where it would be recommended and that particular caution may be warranted for carriers of the APOE ε4 allele.

CONTEXT: Nocturnal vasomotor symptoms (nVMS), depressive symptoms (DepSx), and female reproductive hormone changes contribute to perimenopause-associated disruption in sleep continuity. Hormonal changes underlie both nVMS and DepSx. However, their association with sleep continuity parameters resulting in perimenopause-associated sleep disruption remains unclear.

OBJECTIVE: We aimed to determine the association between female reproductive hormones and perimenopausal sleep discontinuity independent of nVMS and DepSx.

METHODS: Daily sleep and VMS diaries, and weekly serum assays of female reproductive hormones were obtained for 8 consecutive weeks in 45 perimenopausal women with mild DepSx but no primary sleep disorder. Generalized estimating equations were used to examine associations of estradiol, progesterone, and follicle stimulating hormone (FSH) with mean number of nightly awakenings, wakefulness after sleep onset (WASO) and sleep-onset latency (SOL) adjusting for nVMS and DepSx.

RESULTS: Sleep disruption was common (median 1.5 awakenings/night, WASO 24.3 and SOL 20.0 minutes). More awakenings were associated with estradiol levels in the postmenopausal range (β = 0.14; 95% CI, 0.04 to 0.24; P = 0.007), and higher FSH levels (β [1-unit increase] = 0.12; 95% CI, 0.02 to 0.22; P = 0.02), but not with progesterone (β [1-unit increase] = -0.02; 95% CI, -0.06 to 0.01; P = 0.20) in adjusted models. Female reproductive hormones were not associated with WASO or SOL.

CONCLUSION: Associations of more awakenings with lower estradiol and higher FSH levels provide support for a perimenopause-associated sleep discontinuity condition that is linked with female reproductive hormone changes, independent of nVMS and DepSx.

OBJECTIVE: Vasomotor symptoms (VMS), the most frequently reported symptoms during the menopausal transition, have been associated with inflammation. Whether inflammation is a risk factor for or a consequence of VMS remains unclear. The objectives of these analyses were to determine if elevated proinflammatory marker levels were associated with increased incident VMS in women without VMS at baseline and whether these associations varied by menopause transition stage or race/ethnicity.

METHODS: We used longitudinal data on incident VMS, high-sensitivity C-reactive protein (hs-CRP; n = 1,922) and interleukin-6 (IL-6; n = 203) from 13 follow-up visits in the Study of Women's Health Across the Nation, which included five racial/ethnic groups of midlife women. We performed multivariable discrete-time survival analyses to determine adjusted hazard ratios (aHRs) for the association of these proinflammatory markers with incident VMS in women without VMS at baseline.

RESULTS: We found no significant associations of incident VMS with dichotomized hs-CRP (>3 vs ≤3 mg/L) at baseline, concurrent or prior visit (aHRs, 1.04-2.03) or IL-6 (>1.44 vs ≤1.44 pg/mL) at visit 1, concurrent or prior visit (aHRs, 0.67-1.62), or continuous hs-CRP or IL-6 values over 13 follow-up visits (with nonsignificant adjusted increased hazards ranging from 0% to 2%).

CONCLUSIONS: Our results showed no significant association of the proinflammatory biomarkers, hs-CRP or IL-6, either concurrently or with subsequent incident VMS, indicating that inflammation was unlikely to be a risk factor for VMS. Thus, clinical treatments directed at reducing inflammation would be unlikely to reduce the occurrence of VMS.

Spaceflight exposes crewmembers to circadian misalignment and sleep loss, which impair cognition and increase the risk of errors and accidents. We compared the effects of an experimental dynamic lighting schedule (DLS) with a standard static lighting schedule (SLS) on circadian phase, self-reported sleep and cognition during a 45-day simulated space mission. Sixteen participants (mean age [±SD] 37.4 ± 6.7 years; 5 F; n = 8/lighting condition) were studied in four-person teams at the NASA Human Exploration Research Analog. Participants were scheduled to sleep 8 h/night on two weekend nights, 5 h/night on five weekday nights, repeated for six 7-day cycles, with scheduled waketime fixed at 7:00 a.m. Compared to the SLS where illuminance and spectrum remained constant during wake ( 4000K), DLS increased the illuminance and short-wavelength (blue) content of white light ( 6000K) approximately threefold in the main workspace (Level 1), until 3 h before bedtime when illuminance was reduced by  96% and the blue content also reduced throughout ( 4000K × 2 h,  3000K × 1 h) until bedtime. The average (±SE) urinary 6-sulphatoxymelatonin (aMT6s) acrophase time was significantly later in the SLS (6.22 ± 0.34 h) compared to the DLS (4.76 ± 0.53 h) and more variable in SLS compared to DLS (37.2 ± 3.6 min vs. 28.2 ± 2.4 min, respectively, p = .04). Compared to DLS, self-reported sleep was more frequently misaligned relative to circadian phase in SLS RR: 6.75, 95% CI 1.55-29.36, p = .01), but neither self-reported sleep duration nor latency to sleep was different between lighting conditions. Accuracy in the abstract matching and matrix reasoning tests were significantly better in DLS compared to SLS (false discovery rate-adjusted p ≤ .04). Overall, DLS alleviated the drift in circadian phase typically observed in space analog studies and reduced the prevalence of self-reported sleep episodes occurring at an adverse circadian phase. Our results support incorporating DLS in future missions, which may facilitate appropriate circadian alignment and reduce the risk of sleep disruption.

OBJECTIVES: Falls in care home residents have major health and economic implications. Given the impact of lighting on visual acuity, alertness, and sleep and their potential influence on falls, we aimed to assess the impact of upgraded lighting on the rate of falls in long-term care home residents.

DESIGN: An observational study of 2 pairs of care homes (4 sites total). One site from each pair was selected for solid-state lighting upgrade, and the other site served as a control.

SETTING AND PARTICIPANTS: Two pairs of care homes with 758 residents (126,479 resident-days; mean age (±SD) 81.0 ± 11.7 years; 57% female; 31% with dementia).

METHODS: One "experimental" site from each pair had solid-state lighting installed throughout the facility that changed in intensity and spectrum to increase short-wavelength (blue light) exposure during the day (6 am-6 pm) and decrease it overnight (6 pm-6 am). The control sites retained standard lighting with no change in intensity or spectrum throughout the day. The number of falls aggregated from medical records were assessed over an approximately 24-month interval. The primary comparison between the sites was the rate of falls per 1000 resident-days.

RESULTS: Before the lighting upgrade, the rate of falls was similar between experimental and control sites [6.94 vs 6.62 falls per 1000 resident-days, respectively; rate ratio (RR) 1.05; 95% CI 0.70-1.58; P = .82]. Following the upgrade, falls were reduced by 43% at experimental sites compared with control sites (4.82 vs 8.44 falls per 1000 resident-days, respectively; RR 0.57; 95% CI 0.39-0.84; P = .004).

CONCLUSIONS AND IMPLICATIONS: Upgrading ambient lighting to incorporate higher intensity blue-enriched white light during the daytime and lower intensity overnight represents an effective, passive, low-cost, low-burden addition to current preventive strategies to reduce fall risk in long-term care settings.

Human circadian, neuroendocrine, and neurobehavioral responses to light are mediated primarily by melanopsin-containing intrinsically-photosensitive retinal ganglion cells (ipRGCs) but they also receive input from visual photoreceptors. Relative photoreceptor contributions are irradiance- and duration-dependent but results for long-duration light exposures are limited. We constructed irradiance-response curves and action spectra for melatonin suppression and circadian resetting responses in participants exposed to 6.5-h monochromatic 420, 460, 480, 507, 555, or 620 nm light exposures initiated near the onset of nocturnal melatonin secretion. Melatonin suppression and phase resetting action spectra were best fit by a single-opsin template with lambdamax at 481 and 483 nm, respectively. Linear combinations of melanopsin (ipRGC), short-wavelength (S) cone, and combined long- and medium-wavelength (L+M) cone functions were also fit and compared. For melatonin suppression, lambdamax was 441 nm in the first quarter of the 6.5-h exposure with a second peak at 550 nm, suggesting strong initial S and L+M cone contribution. This contribution decayed over time; lambdamax was 485 nm in the final quarter of light exposure, consistent with a predominant melanopsin contribution. Similarly, for circadian resetting, lambdamax ranged from 445 nm (all three functions) to 487 nm (L+M-cone and melanopsin functions only), suggesting significant S-cone contribution, consistent with recent model findings that the first few minutes of a light exposure drive the majority of the phase resetting response. These findings suggest a possible initial strong cone contribution in driving melatonin suppression and phase resetting, followed by a dominant melanopsin contribution over longer duration light exposures.