Publications

STUDY OBJECTIVES: Women in the luteal phase of the menstrual cycle exhibit better cognitive performance overnight than women in the follicular phase, although the mechanism is unknown. Given the link between core body temperature (CBT) and performance, one potential mechanism is the thermoregulatory role of progesterone (P4), estradiol (E2), and their ratio (P4/E2), which change across the menstrual cycle. We examined the role of P4/E2 in modulating performance during extended wake in premenopausal women. Additionally, we compared the acute effects of nighttime light exposure on performance, CBT, and hormones between the menstrual phases.

METHODS: Participants were studied during a 50 h constant routine and a 6.5 h monochromatic nighttime light exposure. Participants were 16 healthy, naturally cycling women (eight follicular; eight luteal). Outcome measures included reaction time, attentional failures, self-reported sleepiness, CBT, melatonin, P4, and E2.

RESULTS: As compared to women in the luteal phase, women in the follicular phase exhibited worse performance overnight. CBT was significantly associated with performance, P4, and P4/E2 but not with other sex hormones. Sex hormones were not directly related to performance. Light exposure that suppressed melatonin improved performance in the follicular phase (n = 4 per group) to levels observed during the luteal phase and increased CBT but without concomitant changes in P4/E2.

CONCLUSIONS: Our results underscore the importance of considering menstrual phase when assessing cognitive performance during sleep loss in women and indicate that these changes are driven predominantly by CBT. Furthermore, this study shows that vulnerability to sleep loss during the follicular phase may be resolved by exposure to light.

CONTEXT: Women are at increased risk for depressive symptoms during the menopause transition. Changes in estradiol secretion and presence of vasomotor symptoms (VMS) contribute to perimenopausal depressive symptoms, but links with progesterone have not been investigated.

OBJECTIVE: To determine whether estradiol variability, ovulatory levels of progesterone, and VMS burden are independently associated with perimenopausal depressive symptomatology.

DESIGN AND INTERVENTION: Depressive symptoms, serum levels of estradiol and progesterone, and VMS frequency were assessed weekly in an 8-week observational study. Association of mood with estradiol variability, ovulatory levels of progesterone, and VMS frequency were estimated using generalized estimating equation models.

SETTING: Academic medical center.

PATIENTS: Fifty unmedicated perimenopausal women with mild-to-moderate depressive symptoms (mean Montgomery-Åsberg Depression Rating Scale [MADRS] score 15.5 ± 5.3).

MAIN OUTCOME MEASURE: Depressive symptoms (MADRS score).

RESULTS: During the study, 90.0% of participants had varying estradiol levels, 51.1% had ovulatory progesterone levels, and 90% had VMS. Greater estradiol variability and absence of progesterone levels consistent with ovulation, but not VMS frequency, are associated with higher levels of depressive symptoms (β = 0.11 [95% confidence interval (95% CI), 0.04 to 0.18; P = 0.001]; β = -2.62 [95% CI, -4.52 to -0.71; P = 0.007], respectively), after accounting for higher body mass index, lifetime history of depression, and stressful life events.

CONCLUSIONS: Increasing dysregulation of ovarian hormones, but not VMS, associates with more depressive symptom burden during perimenopause. These results suggest that perimenopausal mood instability is driven by the underlying hormonal dysregulation of the menopause transition involving changes in both estradiol and progesterone.

OBJECTIVE: Investigate temporal patterns of sleep maintenance problems in women who became surgically menopausal (hysterectomy with bilateral oophorectomy) before their final menstrual period and examine whether presurgery trajectories of sleep maintenance problems are related to problems staying asleep postsurgery.

METHODS: Longitudinal analysis of sleep self-reports collected every 1 to 2 years from 1996 to 2013 from 176 surgically menopausal women in the Study of Women's Health Across the Nation, a seven-site community-based, multiethnic/multiracial, cohort study. Median follow-up was 15.3 years (4.2 years presurgery, 10.2 years postsurgery). Group-based trajectory modeling was used to identify patterns of problems staying asleep, and the presurgery trajectories were used to predict similar postsurgery sleep problems.

RESULTS: Four trajectory patterns of sleep maintenance problems were identified: low (33.5% of women), moderate (33.0%), increasing during presurgery (19.9%), and high (13.6%). One-fifth of women reported a presurgery increase in these problems. Postsurgically, problems staying asleep remained associated with similar levels of presurgical problems, even after adjusting for postsurgical early morning awakening, frequent vasomotor symptoms, and bodily pain score (βlow = -1.716, βmoderate = -1.144, βincreasing = -0.957, βhigh = -1.021; all P values <0.01).

CONCLUSIONS: Sleep maintenance problems were relatively stable across time postsurgery. These data are remarkably consistent with our trajectory results across the natural menopause, suggesting that presurgical assessment of sleep concerns could help guide women's expectations postsurgically. Although reassuring that sleep complaints do not worsen postsurgically for most surgically menopausal women, referral to a sleep specialist should be considered if sleep symptoms persist or worsen after surgery.

BACKGROUND: A test that helps predict the time to the final menstrual period (FMP) has been sought for many years.

OBJECTIVE: To assess the ability of antimullerian hormone (AMH) measurements to predictions the time to FMP.

DESIGN: Prospective longitudinal cohort study.

SETTING: The Study of Women's Health Across the Nation.

PARTICIPANTS AND MEASUREMENTS: AMH and FSH were measured in 1537 pre- or early perimenopausal women, mean age 47.5 ± 2.6 years at baseline, then serially until 12 months of amenorrhea occurred. AMH was measured using a 2-site ELISA with a detection limit of 1.85 pg/mL.

MAIN OUTCOME MEASURE: Areas under the receiver operating curves (AUC) for AMH-based and FSH-based predictions of time to FMP, stratified by age. Probabilities that women would undergo their FMP in the next 12, 24, or 36 months across a range of AMH values were assessed.

RESULTS: AUCs for predicting that the FMP will occur within the next 24 months were significantly greater for AMH-based than FSH-based models. The probability that a woman with an AMH <10 pg/mL would undergo her FMP within the next 12 months ranged from 51% at h<48 years of age to 79% at ≥51 years. The probability that a woman with an AMH >100 pg/mL would not undergo her FMP within the next 12 months ranged from 97% in women <48 years old to 90% in women ≥51 years old.

CONCLUSIONS: AMH measurement helps estimate when a woman will undergo her FMP, and, in general, does so better than FSH.

IMPORTANCE: Biological sex and sociocultural gender represent major sources of diversity among patients, and recent research has shown the association of sex and gender with health. A growing body of literature describes widespread associations of sex and gender with cells, organs, and the manner in which individual patients interact with health care systems. Sex- and gender-informed medicine is a young paradigm of clinical practice and medical research founded on this literature that considers the association of sex and gender with each element of the disease process from risk, to presentation, to response to therapy.

OBSERVATIONS: Characteristics that underlie sex and gender involve both endogenous and exogenous factors that change throughout the life course. This review details clinical examples with broad applicability that highlight sex and gender differences in the key domains of genetics, epigenomic modifiers, hormonal milieu, immune function, neurocognitive aging process, vascular health, response to therapeutics, and interaction with health care systems. These domains interact with one another in multidimensional associations, contributing to the diversity of the sex and gender spectra. Novel research has identified differences of clinical relevance with the potential to improve care for all patients.

CONCLUSIONS AND RELEVANCE: Clinicians should consider incorporating sex and gender in their decision-making to practice precision medicine that integrates fundamental components of patient individuality. Recognizing the biological and environmental factors that affect the disease course is imperative to optimizing care for each patient. Research highlights the myriad ways sex and gender play a role in health and disease. However, these clinically relevant insights have yet to be systematically incorporated into care. The framework described in this review serves as a guide to help clinicians consider sex and gender as they practice precision medicine.

Our study objectives were to evaluate the age-related changes in actigraphy measures of sleep duration, continuity, and timing across 12 years in midlife women as they traversed the menopause, and to take into account factors affecting women's sleep that also change with age. Black, white, and Chinese women were recruited from the Study of Women's Health Across the Nation (SWAN) to participate in an ancillary sleep study on two occasions over 3 years apart and a third assessment 12 years after the first (N = 300, mean ages, 52, 55, and 64 at the three assessments). Women had at least four consecutive nights of actigraphy (95% with 7 nights) and sleep diaries, and self-reported sleep complaints measured at each time point. Partial correlations adjusted for time between assessments across the 12 years were significant and moderate in size (r's = .33-.58). PROC MIXED/GLIMMIX multivariate models showed that sleep duration increased over time; wake after sleep onset (WASO) declined, midpoint of sleep interval increased, and sleep latency and number of sleep complaints did not change between the first and third assessments. Blacks and whites had a greater increase in sleep duration than Chinese. Taken together, the results of this longitudinal study suggest that sleep may not worsen, in general, in midlife women. Perhaps, the expected negative effect of aging in midlife into early old age on sleep is overstated.

OBJECTIVE: The Menopause Strategies: Finding Lasting Answers for Symptoms and Health clinical trials network was funded by the National Institutes of Health to find new ways to alleviate the most common, bothersome menopausal symptoms by designing and conducting multiple concurrent clinical intervention studies, accommodating a wide scope of populations and intervention strategies.

METHODS: Trials were conducted in Boston, Indianapolis, Minneapolis, Oakland, Philadelphia, and Seattle, with the Data Coordinating Center in Seattle, and were designed with standardized eligibility criteria and endpoints. Primary outcomes focused on vasomotor symptoms, sleep quality and insomnia symptoms, and vaginal symptoms. Secondary outcomes included quality of life, sexual function, and mood.

RESULTS: We completed five randomized clinical trials and three ancillary studies, testing nine interventions in over 1,300 women and collecting nearly 16,000 bio-specimens. Escitalopram, venlafaxine hydrochloride extended release, and low-dose estradiol diminished hot flashes by approximately 50% as compared with a 30% decrease by placebo. No benefits on vasomotor symptoms were observed with yoga or exercise compared with usual activity, nor with omega-3 supplementation compared with placebo. Cognitive behavioral therapy for insomnia reduced self-reported insomnia symptoms and improved overall sleep quality compared with menopause education control. We did not find significant benefit from a vaginal estradiol tablet or a vaginal moisturizer compared with placebo tablet and gel in diminishing the severity of vaginal symptoms.

CONCLUSIONS: The MsFLASH trials contributed substantially to our understanding of bothersome menopausal symptom treatment. It is important that clinicians counseling women about available treatment options consider all therapies-both nonhormonal and hormonal.

OBJECTIVES: To test the effect of perceived sleep duration on cognitive performance.

METHODS: Sixteen healthy individuals [8F; mean age (± SD): 24.2 ± 3.0 years)] received an 8-h sleep opportunity followed by a 5-h opportunity on two consecutive nights. Upon waking, they were randomized to being informed that they received either an 8-h or 5-h sleep opportunity, via a clock that ran either fast, slow or normally. Cognitive performance was assessed using 10-min auditory psychomotor vigilance tests and subjective sleepiness ratings. Homeostatic and circadian sleep drive was assessed using waking electroencephalography (EEG).

RESULTS: Reaction time was significantly quicker when individuals thought that they had slept for 8 h but given a 5-h sleep opportunity. Conversely, reaction times were significantly slower when individuals thought they had 5 h of sleep but given an 8-h sleep opportunity. EEG delta power (1.0-4.5 Hz) during wake increased significantly when sleep was restricted to 5 h, and individuals thought they slept for 5 h, but this increase was attenuated with a perceived sleep duration of 8 h following a 5-h opportunity. EEG delta power did not increase, however, with perceived sleep restriction. EEG high-alpha activity (10.5-11.5 Hz) was consistently higher when participants thought that they had an 8-h sleep opportunity, regardless of the actual duration.

CONCLUSIONS: These results suggest that perceived sleep duration may modulate psychosomatic responses. Additional studies with predefined outcomes and analyses are necessary to confirm these findings, which may have important implications for understanding how sleep affects cognition and psychosomatic responses.