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Studies suggest that female reproductive hormones are under circadian regulation, although methodological differences have led to inconsistent findings. To determine whether circulating levels of reproductive hormones exhibit circadian rhythms. Blood samples were collected across ∼90 consecutive hours, including 2 baseline days under a standard sleep-wake schedule and ∼50 hours of extended wake under constant routine (CR) conditions. Intensive Physiological Monitoring Unit, Brigham and Women's Hospital. Seventeen healthy premenopausal women (22.8 ± 2.6 years; nine follicular; eight luteal). Fifty-hour CR. Plasma estradiol (E2), progesterone (P4), LH, FSH, SHBG, melatonin, and core body temperature. All hormones exhibited significant 24-hour rhythms under both standard sleep-wake and CR conditions during the follicular phase (P < 0.05). In contrast, only FSH and SHBG were significantly rhythmic during the luteal phase. Rhythm acrophases and amplitudes were similar between standard sleep-wake and CR conditions. The acrophase occurred in the morning for P4; in the afternoon for FSH, LH, and SHBG; and during the night for E2. Our results confirm previous reports of ∼24-hour rhythms in many female reproductive hormones in humans under ambulatory conditions but demonstrate that these hormones are under endogenous circadian regulation, defined as persisting in the absence of external time cues. These results may have important implications for the effects of circadian disruption on reproductive function.

We studied the dynamics of melatonin suppression and changes in cortisol levels in humans in response to light exposure at night using high-frequency blood sampling. Twenty-one young healthy participants were randomized to receive either intermittent bright (~9,500 lux) light (IBL), continuous bright light (CBL) or continuous dim (~1 lux) light (VDL) for 6.5 h during the biological night (n = 7 per condition). Melatonin suppression occurred rapidly within the first 5 min and continued until the end of each IBL stimuli (t 1/2  = ~13 min). Melatonin recovery occurred more slowly between IBL stimuli (half-maximal recovery rate of ~46 min). Mean melatonin suppression (~40%) and recovery (~50%) were similar across IBL stimuli. Suppression dynamics under CBL were also rapid (t 1/2  = ~18 min), with no recovery until the light exposure ended. There was a significant linear increase of cortisol levels between the start and end of each IBL stimulus. Under CBL conditions cortisol showed trimodal changes with an initial linear activating phase, followed by an exponential inhibitory phase, and a final exponential recovery phase. These results show that light exposure at night affects circadian driven hormones differently and that outcomes are influenced by the duration and pattern of light exposure.

Abstract This White Paper presents the results from a workshop cosponsored by the Sleep Research Society (SRS) and the Society for Research on Biological Rhythms (SRBR) whose goals were to bring together sleep clinicians and sleep and circadian rhythm researchers to identify existing gaps in diagnosis and treatment and areas of high-priority research in circadian rhythm sleep–wake disorders (CRSWD). CRSWD are a distinct class of sleep disorders caused by alterations of the circadian time-keeping system, its entrainment mechanisms, or a misalignment of the endogenous circadian rhythm and the external environment. In these disorders, the timing of the primary sleep episode is either earlier or later than desired, irregular from day-to-day, and/or sleep occurs at the wrong circadian time. While there are incomplete and insufficient prevalence data, CRSWD likely affect at least 800,000 and perhaps as many as 3 million individuals in the United States, and if Shift Work Disorder and Jet Lag are included, then many millions more are impacted. The SRS Advocacy Taskforce has identified CRSWD as a class of sleep disorders for which additional high-quality research could have a significant impact to improve patient care. Participants were selected for their expertise and were assigned to one of three working groups: Phase Disorders, Entrainment Disorders, and Other. Each working group presented a summary of the current state of the science for their specific CRSWD area, followed by discussion from all participants. The outcome of those presentations and discussions are presented here.

Abstract 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.

While studies suggest that light and feeding patterns can reset circadian rhythms in various metabolites, whether these shifts follow a predictable pattern is unknown. We describe the first phase response curves (PRC) for lipids and hepatic proteins in response to combined light and food stimuli. The timing of plasma rhythms was assessed by constant routine before and after exposure to a combined 6.5-hour blue light exposure and standard meal schedule, which was systematically varied by ~20° between individuals. We find that the rhythms shift according to a PRC, with generally greater shifts for lipids and liver proteins than for melatonin. PRC timing varies relative to the stimulus, with albumin and triglyceride PRCs peaking at a time similar to melatonin whereas the cholesterol and high-density lipoprotein PRCs are offset by ~12 h. These data have important implications for treating circadian misalignment in shiftworkers who consume meals and are exposed to light around the clock. A key property of circadian rhythms is that they can be reset in response to environmental time cues; this response is described by a Phase Response Curve (PRC). Here the authors describe PRCs for resetting circadian rhythms in lipids and hepatic proteins in response to combined light and food exposure.

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.

Abstract Context Perturbations to the hypothalamic-pituitary-adrenal (HPA) axis have been hypothesized to increase postmenopausal cardiometabolic risk. Although sleep disturbance, a known risk factor for cardiometabolic disease, is prevalent during the menopause transition, it is unknown whether menopause-related sleep disturbance and estradiol decline disturb the HPA axis. Objective We examined the effect of experimental fragmentation of sleep and suppression of estradiol as a model of menopause on cortisol levels in healthy young women. Methods Twenty-two women completed a 5-night inpatient study during the mid-to-late follicular phase (estrogenized). A subset (n = 14) repeated the protocol after gonadotropin-releasing hormone agonist-induced estradiol suppression. Each inpatient study included 2 unfragmented sleep nights followed by 3 experimental sleep fragmentation nights. This study took place with premenopausal women at an academic medical center. Interventions included sleep fragmentation and pharmacological hypoestrogenism, and main outcome measures were serum bedtime cortisol levels and cortisol awakening response (CAR). Results Bedtime cortisol increased 27% (P = .03) and CAR decreased 57% (P = .01) following sleep fragmentation compared to unfragmented sleep. Polysomnographic-derived wake after sleep-onset (WASO) was positively associated with bedtime cortisol levels (P = .047) and negatively associated with CAR (P < .01). Bedtime cortisol levels were 22% lower in the hypoestrogenized state compared to the estrogenized state (P = .02), while CAR was similar in both estradiol conditions (P = .38). Conclusion Estradiol suppression and modifiable menopause-related sleep fragmentation both independently perturb HPA axis activity. Sleep fragmentation, commonly seen in menopausal women, may disrupt the HPA axis, which in turn may lead to adverse health effects as women age.

Abstract Objectives Fatigue is a common nonhematologic toxicity of the CDK4/6 inhibitor palbociclib in metastatic breast cancer (MBC) patients with prevalence rates of clinician-rated all-grade and grade 3/4 fatigue of 39.2% and 2.5%, respectively. We prospectively assessed the incidence of fatigue emerging on palbociclib using patient-reported measures and explored potential predictors. Methods Eighty-eight patients with HR+ HER2− MBC without fatigue initiating palbociclib with endocrine therapy were assessed before and monthly across the initial 6 cycles. Clinically meaningful levels of patient-reported fatigue (Functional Assessment of Chronic Illness Therapy Fatigue Scale, FACIT-F < 34), severity of, and functional interference due to fatigue (NCI Patient-Reported Outcomes for CTCAE, PRO-CTCAE) were assessed. Hematologic and nonhematologic predictors were examined pretreatment and concurrent with fatigue assessments. Results Patient-reported fatigue emerged in 21/88 patients [incidence rate 23.9% (95%CI, 15.4%-34.1%)] within 2.8 ± 1.7 treatment cycles. PRO-CTCAE-rated incidence rate of severe fatigue and fatigue interference was 14.8% (95%CI, 8.1%-23.9%) and 10.2% (95%CI, 4.8%-18.5%), respectively. Lower pretreatment absolute neutrophil count (ANC) levels predicted treatment-emergent fatigue (P =.01), but ANC levels on treatment did not (P =.78). Other pretreatment predictors were long sleep duration (P =.02) and low physical activity (trend, P =.07). Treatment-emergent fatigue was associated with objectively measured long sleep duration on treatment (P =.02), but not other measures (P ≥.35). Conclusions One-quarter of patients with HR+ HER2− MBC initiating palbociclib report rapidly emergent clinically meaningful fatigue, often with severe symptoms and functional interference. Treatment-emergent fatigue is associated with both pretreatment (lower ANC levels, longer sleep duration) and on-treatment (long sleep duration) hematologic and nonhematologic profiles.