Publications

Background Cardiovascular disease (CVD) in women has unique features, including associations with reproductive factors that are incompletely understood. Vasomotor symptoms (VMS), the classic menopausal symptom, are linked to CVD risk factors and subclinical CVD. Evidence linking VMS to CVD events is limited. We tested whether frequent and/or persistent VMS were associated with increased risk for fatal and nonfatal CVD events in SWAN (Study of Women's Health Across the Nation). Methods and Results A total of 3083 women, aged 42 to 52 years at baseline, underwent up to 16 in-person visits over 22 years. Assessments included questionnaires on VMS frequency (0, 1-5, or ≥6 days/2 weeks), physical measures, phlebotomy, and reported CVD events (myocardial infarction, stroke, heart failure, and revascularization). A subset of events was adjudicated via medical record. Death certificates were obtained. Relationships between baseline VMS or persistent VMS over the follow-up (proportion of visits with frequent VMS) with combined incident nonfatal and fatal CVD were tested in Cox proportional hazards models adjusted for demographics, medication use, and CVD risk factors. Participants experienced 231 CVD events over the follow-up. Women with frequent baseline VMS had an elevated risk of subsequent CVD events (relative to no VMS; ≥6 days: hazard ratio [HR] [95% CI], 1.51 [1.05-2.17], P=0.03; 1-5 days: HR [95% CI], 1.02 [0.75-1.39], P=0.89, multivariable). Women with frequent VMS that persisted over time also had an increased CVD event risk (>33% versus ≤33% of visits: HR [95% CI], 1.77 [1.33-2.35], P<0.0001, multivariable). Conclusions Frequent and persistent VMS were associated with increased risk of later CVD events. VMS may represent a novel female-specific CVD risk factor.

STUDY OBJECTIVES: To determine whether actigraphy-assessed indices of sleep are associated with cognitive performance in women, and explore whether these associations vary by race/ethnicity.

METHODS: Participants were 1,126 postmenopausal community-dwelling females (mean age 65 years) from the observational Study of Women's Health Across the Nation (SWAN); 25% were black, 46% white, 13% Chinese, 11% Japanese, and 5% Hispanic. Actigraphy-assessed sleep measures included total sleep time, wake after sleep onset (WASO), and fragmentation. Cognitive measures included immediate and delayed verbal memory, working memory, and information processing speed. All measures were assessed in conjunction with SWAN annual visit 15.

RESULTS: Across the sample, after covariate adjustment, greater WASO and fragmentation were concurrently associated with slower information processing speed. Black participants had significantly worse sleep relative to other race/ethnic groups. Significant race/sleep interactions were observed; in black, but not white, participants, greater fragmentation was concurrently associated with worse verbal memory and slower information processing speed, and greater WASO was concurrently associated with slower information processing speed. Sleep-cognitive performance associations were not different in Chinese and Japanese participants relative to white participants.

CONCLUSIONS: Greater wakefulness and fragmentation during sleep are concurrently associated with slower information processing. Sleep continuity impacted concurrent cognitive performance in black, but not white, women. This effect may not have been detected in white women because their sleep was largely within the normal range. Future longitudinal studies in diverse samples are critical to further understand whether race/ethnicity moderates the influence of sleep on cognitive performance.

Major depressive disorder (MDD) has a higher prevalence in women with supraphysiologic androgen levels. Whether there is also an association between depression and androgen levels in the physiological range, is unknown. This study examined if women with current MDD have higher androgen levels compared to women who have never had MDD, and if androgen levels are associated with onset and remission of MDD. In 1659 women (513 current MDD, 754 remitted MDD, and 392 never MDD), baseline plasma levels of total testosterone, 5α-dihydrotestosterone, and androstenedione were determined with liquid chromatography-tandem mass spectrometry, and dehydroepiandrosterone-sulfate and sex hormone binding globulin (SHBG) with radioimmunoassays. Free testosterone was calculated. MDD status was assessed at baseline, and at 2 and 4 years follow-up. Women were aged between 18 and 65 years (mean age 41) with total testosterone levels in the physiological range (geometric mean 0.72 nmol/L [95% CI 0.27-1.93]). After adjusting for covariates and multiple testing, women with current MDD had a higher mean free testosterone than women who never had MDD (adjusted geometric mean 8.50 vs. 7.55 pmol/L, p = 0.0005), but this difference was not large enough to be considered clinically meaningful as it was consistent with statistical equivalence. Levels of other androgens and SHBG did not differ and were also statistically equivalent between the groups. None of the androgens or SHBG levels predicted onset or remission of MDD. Our findings support the idea that plasma androgens within the physiological range have no or only limited effects on depressive disorders in women.

We tested the effect of daytime indoor light exposure with varying melanopic strength on cognitive performance in college-aged students who maintained an enforced nightly sleep opportunity of 7 h (i.e., nightly sleep duration no longer than 7 h) for 1 week immediately preceding the day of light exposure. Participants (n = 39; mean age ± SD = 24.5 ± 3.2 years; 21 F) were randomized to an 8 h daytime exposure to one of four white light conditions of equal photopic illuminance ( 50 lux at eye level in the vertical plane) but different melanopic illuminance [24-45 melanopic-EDI lux (melEDI)] generated by varying correlated color temperatures [3000K (low-melEDI) or 5000K (high-melEDI)] and spectra [conventional or daylight-like]. Accuracy on a 2-min addition task was 5% better in the daylight-like high-melEDI condition (highest melEDI) compared to the conventional low-melEDI condition (lowest melEDI; p < 0.01). Performance speed on the motor sequence learning task was 3.2 times faster (p < 0.05) during the daylight-like high-melEDI condition compared to the conventional low-melEDI. Subjective sleepiness was 1.5 times lower in the conventional high-melEDI condition compared to the conventional low-melEDI condition, but levels were similar between conventional low- and daylight-like high-melEDI conditions. These results demonstrate that exposure to high-melanopic (short wavelength-enriched) white light improves processing speed, working memory, and procedural learning on a motor sequence task in modestly sleep restricted young adults, and have important implications for optimizing lighting conditions in schools, colleges, and other built environments.

CONTEXT: Dyslipidemia and cardiovascular disease are common in shift workers and eating at night may contribute to this pathophysiology.

OBJECTIVE: To examine the effects of eating at different times of day on lipid profiles.

DESIGN: Two 24-hour baseline days with 8 hours of sleep, 3 meals (breakfast, lunch, dinner) and a snack, followed by a 40-hour constant routine (CR) with hourly isocaloric meals.

SETTING: Intensive Physiological Monitoring Unit, Brigham and Women's Hospital.

PARTICIPANTS: Twenty-one healthy adults [23.4 ± 2.7 years, 5F].

INTERVENTION: Forty-hour CR.

MAIN OUTCOME MEASURES: A standard clinical lipid panel, consisting of total cholesterol, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), was assayed in blood samples collected 4-hourly across  4 days.

RESULTS: When participants ate at night, levels of TG were similar to eating during the day, however, these levels at night were reached with consuming approximately half the calories. Additionally, 24-hour levels of TG were 10% higher when meals were consumed hourly across 24 hours compared to consuming a typical 3-meal schedule while awake during the day and sleeping at night. The endogenous circadian rhythms of TG, which peaked at night, were shifted earlier by  10 hours under baseline conditions, whereas the rhythms in total cholesterol, HDL-C, and LDL-C remained unchanged and peaked in the afternoon.

CONCLUSIONS: The time-of-day dependency on postprandial lipid metabolism, which leads to hypersensitivity in TG responses when eating at night, may underlie the dyslipidemia and elevated cardiovascular disease risk observed in shift workers.

OBJECTIVES: Extended-duration work rosters (EDWRs) with shifts of 24+ hours impair performance compared with rapid cycling work rosters (RCWRs) that limit shifts to 16 hours in postgraduate year (PGY) 1 resident-physicians. We examined the impact of a RCWR on PGY 2 and PGY 3 resident-physicians.

METHODS: Data from 294 resident-physicians were analyzed from a multicenter clinical trial of 6 US PICUs. Resident-physicians worked 4-week EDWRs with shifts of 24+ hours every third or fourth shift, or an RCWR in which most shifts were ≤16 consecutive hours. Participants completed a daily sleep and work log and the 10-minute Psychomotor Vigilance Task and Karolinska Sleepiness Scale 2 to 5 times per shift approximately once per week as operational demands allowed.

RESULTS: Overall, the mean (± SE) number of attentional failures was significantly higher (P =.01) on the EDWR (6.8 ± 1.0) compared with RCWR (2.9 ± 0.7). Reaction time and subjective alertness were also significantly higher, by ∼18% and ∼9%, respectively (both P <.0001). These differences were sustained across the 4-week rotation. Moreover, attentional failures were associated with resident-physician-related serious medical errors (SMEs) (P =.04). Although a higher rate of SMEs was observed under the RCWR, after adjusting for workload, RCWR had a protective effect on the rate of SMEs (rate ratio 0.48 [95% confidence interval: 0.30-0.77]).

CONCLUSIONS: Performance impairment due to EDWR is improved by limiting shift duration. These data and their correlation with SME rates highlight the impairment of neurobehavioral performance due to extended-duration shifts and have important implications for patient safety.

OBJECTIVE: Vasomotor symptoms (VMS) (hot flashes and night sweats) affect most women over the menopause transition. Comparing the safety and effectiveness of treatments for vasomotor symptoms is limited by the use of inconsistent outcome measures, and uncertainty as to which outcomes are most important to symptomatic women. To address this, we have developed a Core Outcome Set (COS) for use in clinical trials of treatments for VMS.

METHODS: We systematically reviewed the primary outcomes measured in randomized controlled trials of treatments for VMS. These were refined and entered into a two-round modified Delphi survey completed by clinicians, researchers, and postmenopausal women between November 2019 and March 2020. Outcomes were scored on a nine-point scale from "not important" to "critically important." Two international consensus meetings were held to finalize the COS.

RESULTS: Based on the systematic review, 13 separate outcomes were included in the Delphi process. This was completed by 227 participants of whom 58% were postmenopausal women, 34% clinicians, and 8% researchers. Predefined thresholds were applied to categorize importance scores obtained during Round 2 of the Delphi survey. These informed discussions at the consensus meetings which were attended by 56 participants from 28 countries. The final COS includes six outcomes: 1) frequency of VMS, 2) severity of VMS, 3) distress, bother or interference caused by VMS, 4) impact on sleep, 5) satisfaction with treatment, and 6) side-effects of treatment.

CONCLUSION: Implementation of this COS will: better enable research studies to accurately reflect the joint priorities of postmenopausal women, clinicians and researchers, standardize outcome reporting, and facilitate combining and comparing results from different studies, and ultimately improve outcomes for women with bothersome VMS.

OBJECTIVE: Irritability is a highly burdensome complaint, commonly, but not universally, linked with depressive symptoms. While increased variability in estradiol has been associated with depressive symptoms during perimenopause, more insight is needed into reproductive hormone dynamics and other factors that predispose perimenopausal women to irritable mood.

METHODS: Among 50 mildly depressed perimenopausal women (mean (SD) age 48.4 (3.9) years), severity of irritability symptoms (on Symptom Questionnaire Hostility subscale, range 0-23) was assessed weekly for eight weeks, concurrent with potential predictors. Associations between these were examined using generalized estimating equating models.

RESULTS: Most women (82.0%) reported having moderate to severe irritability at least once. However, the severity of irritability was highly variable from week-to-week (between-subject mean coefficient of variation [CV] 72.9% and within-subject mean CV 63.7%). In multivariate analyses, less variable serum estradiol levels (standardized β within-person CV -0.23 95%CI [-0.32, -0.14], p < 0.001), greater depression severity (0.45 [0.35, 0.56], p < 0.001), younger age (-0.23, [-0.28, -0.09], p < 0.001), and more frequent vasomotor symptoms (0.14 [0.05, 0.23], p = 0.002) were associated with more irritability. Depression severity explained the largest portion of the variance in irritability, but still not more than 20.3%. Neither crude values, weekly change in, or variability of progesterone or FSH levels were associated with irritability.

CONCLUSIONS: Irritability was highly prevalent among mildly depressed perimenopausal women. In contrast to depressive symptoms, decreased rather than increased variability in estradiol levels was associated with more irritability. This highlights that irritable mood can be disentangled from depressive symptoms in perimenopausal women and might be linked with different estradiol dynamics.

OBJECTIVE: To examine the effects of prescription sleep medications on patient-reported sleep disturbances.

DESIGN: Retrospective cohort.

SETTING: Longitudinal cohort of community-dwelling women in the USA.

PARTICIPANTS: Racially and ethnically diverse middle-aged women who reported a sleep disturbance.

INTERVENTIONS: New users of prescription sleep medications propensity score matched to women not starting sleep medications.

MAIN OUTCOMES AND MEASURES: Self-reported sleep disturbance during the previous 2 weeks-difficulty initiating sleep, waking frequently and early morning awakening-using a 5-point Likert scale, ranging from no difficulty on any night (rating 1) to difficulty on 5 or more nights a week (rating 5). Sleep disturbances were compared at 1 year (primary outcome) and 2 years of follow-up.

RESULTS: 238 women who started sleep medications were matched with 447 non-users. Participants had a mean age of 49.5 years and approximately half were white. At baseline, sleep disturbance ratings were similar: medication users had a mean score for difficulty initiating sleep of 2.7 (95% CI 2.5 to 2.9), waking frequently 3.8 (95% CI 3.6 to 3.9) and early morning awakening 2.8 (95% CI 2.6 to 3.0); non-users ratings were 2.6 (95% CI 2.5 to 2.7), 3.7 (95% CI 3.6 to 3.9) and 2.7 (95% CI 2.6 to 2.8), respectively. After 1 year, ratings for medication users were 2.6 (95% CI 2.4 to 2.8) for initiating sleep, 3.6 (95% CI 3.4 to 3.8) for waking frequently and 2.8 (95% CI 2.6 to 3.0) for early morning awakening; for non-users, the mean ratings were 2.3 (95% CI 2.2 to 2.5), 3.5 (95% CI 3.3 to 3.6) and 2.5 (95% CI 2.3 to 2.6), respectively. None of the 1 year changes were statistically significant nor were they different between medication users and non-users. Two-year follow-up results were consistent, without statistically significant reductions in sleep disturbance in medication users compared with non-users.

CONCLUSIONS: These analyses suggest that women who initiated sleep medications rated their sleep disturbances similar after 1 and 2 years. The effectiveness of long-term sleep medication use should be re-examined.