BACKGROUND:The cortisol awakening response (CAR) has two regulatory pathways underlying its components typically not discriminated in CAR studies. The timing of the peak, post-peak secretion and overall levels were assessed in relation to health in this directional hypothesis-driven study. METHOD:Healthy females (N = 61, aged 18-38 years) collected saliva at awakening and three further 15-min intervals over seven consecutive days in their domestic setting. Awakening and saliva sampling times were electronically monitored (EM). Participants provided self-reported sampling times as well as demographics and health status. Analyses were conducted for 56 participants providing full cortisol and health data. Participants were categorised as 'healthy' (N = 34; 61%) or 'less healthy' (N = 22; 39%) based on their self-ratings. RESULTS:Multilevel modelling using 'real time' sampling (EM-estimated) revealed significant cortisol growth curve shape differences between health groups. In comparison to the less healthy group, the healthy group showed lower secretion rates in the final sampling (3rd to 4th) interval with more negative rates (declines) and lower mean cortisol (over 7 study days and 4 samples). The less healthy had more final sample (later) peak cortisol concentrations. Receiver Operating Characteristic (ROC) analyses of CAR composite measures (decline, peak time, and mean levels) were conducted to optimise health status discrimination. Lower third to fourth sample secretion rate was the strongest discriminator, correctly detecting the health status of 71% of all participants. Lower cortisol concentration explained 68% and higher percentage of days with final (fourth) sample peaks explained 61%. Maximum detection was achieved by a combined decision criterion which correctly identified exactly three-quarters (75%) of cases. Findings were robust to known cortisol covariates. CONCLUSION:This novel CAR analysis offers insight into potential health vulnerability in younger healthy populations, perhaps an early indicator of hypothalamic-pituitary-adrenal (HPA) axis dysfunction.

Stress activates the hypothalamic-pituitary-adrenal (HPA) axis of which cortisol is an end product. ‘Allostatic load’ is where systems including the HPA axis are exposed to high, cumulative, physiologic burdens (such as chronic breathlessness) leading to flatter diurnal cortisol slopes and poorer health outcomes. The aim of this hypothesis-generating study explored longitudinal changes in cortisol secretion and any associated changes in breathlessness after introducing regular, low dose morphine or placebo. This was an optional, hypothesis-generating sub-study embedded in a multi-site, randomised, double-blind, placebo-controlled trial (RCT) of regular, low-dose morphine for chronic breathlessness and chronic obstructive pulmonary disease. In a blinded dose-increment algorithm by week three, doses were 0 mg-32 mg. Participants in the RCT could elect to continue in a six-month blinded extension. This sub-study excluded people who used non-inhaled corticosteroids in the previous month or were on subcutaneous insulin. Participants collected saliva for cortisol assays for two days at baseline, and ends of weeks 1, 3 and 12 at 3,6 and 12 h after waking, generating sufficient data to calculate diurnal cortisol slopes and areas under the curve (AUC). Samples were analysed using ELISA. Correlations between diurnal cortisol profiles (slope and AUC) and a range of measures were explored. Twenty mostly female former smokers were in this sub-study. At baseline and the end of week 1, one-way ANOVA between-group analyses showed no significant differences in the log-transformed cortisol slope or ln-AUC. There was a strong correlation between the age-adjusted Charlson Comorbidity Index (CCI) and ln-AUC (r=-0.70, p < 0.001) and moderate correlation with age (r=-0.43, p = 0.06). In the blinded extension study, there was a self-selecting blinded group (n = 7) all on active medication. Global impression of change (GIC) was highly correlated with the diurnal cortisol slope (rs = 0.98, p = 0.01), and with decrease in average breathlessness (r = 0.89, p = 0.04). This hypothesis-generating study did not show a relationship between the diurnal cortisol profile and morphine in people with chronic breathlessness and COPD. For the sub-group still on study at 12weeks, the cortisol curves became steeper as average breathlessness decreased and as global impression of change (GIC) improved, suggesting that reducing breathlessness may potentially positively impact the HPA axis in a sub-group of people. Registration Number NCT02720822 date registered 28/03/2016.

In healthy individuals, the majority of cortisol secretion occurs within several hours surrounding morning awakening. A highly studied component of this secretory period is the cortisol awakening response (CAR), the rapid increase in cortisol levels across the first 30 to 45 minutes after morning awakening. This strong cortisol burst at the start of the active phase has been proposed to be functional in preparing the organism for the challenges of the upcoming day. Here, we review evidence on key regulatory and functional processes of the CAR and develop an integrative model of its functional role. Specifically, we propose that, in healthy individuals, the CAR is closely regulated by an intricate dual-control system, which draws upon key circadian, environmental, and neurocognitive processes to best predict the daily need for cortisol-related action. Fine-tuned CAR expression, in turn, is then assumed to induce potent glucocorticoid action via rapid nongenomic and slower genomic pathways (eg, affecting circadian clock gene expression) to support and modulate daily activity through relevant metabolic, immunological, and neurocognitive systems. We propose that this concerted action is adaptive in mediating two main functions: a primary process to mobilize resources to meet activity-related demands and a secondary process to help the organism counterregulate adverse prior-day emotional experiences.

Cortisol awakening response (CAR) research relies upon self-collected saliva sampling during the post-awakening period. It is unknown how the CAR protocol is perceived and how they may affect typical routines relevant to CAR methodology. CAR assessment is sensitive to state variables, suggesting that CAR measurement may be affected by research participation. This is the first qualitative study to explore motivation and experiences of participation in CAR research.Interviews were conducted with a sample of 20 participants (males/females: 4/16) aged 46-82 years following their participation in CAR research in the domestic setting. Responses were transcribed verbatim and thematically analysed.Participants were motivated to take part in CAR research for altruistic reasons and the apparent convenience of undertaking the study at home. Participants experienced the study as arduous describing apprehension and the cognitive burden it placed on them leading to disruptions to sleep and morning routines. Participants also struggled to identify the moment of awakening and there was uncertainty surrounding the timing of the first awakening sample. Disruptions were lessened with habituation to sampling on repeated study days.There was apprehension about taking part in CAR research, affecting mood, cognition, and sleep; state variables known to influence the CAR. Findings inform ways to optimise CAR ‘ecological validity’ and obtain typical CAR characteristics. The ‘moment of awakening’, was not universally understood, leading to hesitancy in deciding when to collect saliva samples. Researchers need to include a specific discussion of the commonly experienced ambiguity surrounding awakening to increase awareness, lessen anxiety and highlight its importance.

Primary open angle glaucoma (POAG) may be the principal ocular disease that effects photic input to the circadian time-keeping system. The current study is the first to monitor sailvary post-awakening cortisol secretion in those diagnosed with POAG. 54, male (N=16) and female (N=38) participants with POAG were recruited from the International Glaucoma Association following a call for participants advertised in a monthly newsletter. Ages ranged from 46-84 years (70.3 ±7.3). Participants collected saliva samples on two consecutive weekdays at 0, 15, 30, and 45 minutes post awakening following best practice guidelines and completed the National Eye Institute Visual Function Questionnaire. Post awakening cortisol concentrations ranged between 0.36 and 51.23 nmol/L within a healthy, normal range. Analyses revealed a typical CAR profile, with a significant increase in cortisol over 45 minutes. Further there was a negative association between the CAR and the measure of visual function indicating that those with lower visual function had a greater CAR. The CAR was preserved for participants with primary open angle glaucoma despite reduced photic sensitivity. Participants who reported poorer visual function exhibited a higher CAR suggesting that a boost was needed to help them meet demands they face due to reduced quality of vision.

Cortisol awakening response (CAR) research relies upon precise self-collected saliva sampling during sleep inertia in the immediate post-awakening period. It remains unknown how these study demands are perceived by participants and how they may affect typical routines relevant to CAR methodology. CAR assessment is sensitive to levels of arousal and anticipations of the day ahead, meaning that CAR measurement may be affected by research participation. This is the first qualitative study to explore the motivations and experience of participants taking part on CAR research. A sample of 20 participants (males/females: 4/16) aged 46-82 years were interviewed. Interviews covered participant's motivations and experiences following their participation in CAR research. Transcripts were analysed thematically. Participants were motivated to take part in CAR research for altruistic and apparent convenience of undertaking the study at home. Participants experienced the study as being arduous in terms of apprehension, the cognitive burden it placed on them and disruptions to sleep and routine. These disruptions were lessened with habituation from repeated days of sampling. Participants had difficulty describing and identifying the moment of awakening and there was uncertainty about taking the first sample on time. Researchers should be aware of the negative impact of participation in CAR research. In preparation for potential diffculties, efforts should be made to lessen participant anxiety during the induction. Induction also needs to include discussion of ambiguity surrounding awakening. It is recommended researchers repeat the study over 3 consecutive days enabling habituation to sampling protocol.

Parkinson’s Disease (PD) is a prevalent and complex age-related neurodegenerative condition for which there are no disease-modifying treatments currently available. The pathophysiological process underlying PD remains incompletely understood but increasing evidence points to multiple system dysfunction. Interestingly, the past decade has produced evidence that exercise not only reduces signs and symptoms of PD but is also potentially neuroprotective. Characterizing the mechanistic pathways that are triggered by exercise and lead to positive outcomes will improve understanding of how to counter disease progression and symptomatology. In this review, we highlight how exercise regulates the neuroendocrine system, whose primary role is to respond to stress, maintain homeostasis and improve resilience to aging. We focus on a group of hormones – cortisol, melatonin, insulin, klotho, and vitamin D – that have been shown to associate with various non-motor symptoms of PD, such as mood, cognition, and sleep/circadian rhythm disorder. These hormones may represent important biomarkers to track in clinical trials evaluating effects of exercise in PD with the aim of providing evidence that patients can exert some behavioral-induced control over their disease.

Parenting adolescents requires parents to display diverse competencies, and parenting competence i.e. «caregiving» may be affected differentially by the underlying dimensions of an individual's «care seeking» behaviour, i.e. their own attachment style. Twenty five mothers of adolescent daughters were recruited in a cross-sectional design for this pilot study. Mothers aged between 32-51 years with a mean (± SD) age of 44.72 (± 5.47) years and each completed the Parenting Role Interview, which provides an «investigator-based» as-sessment of their parenting competence, as well as self-report measures of attachment style, stress, depression and well-being. Results revealed that greater parenting competence was associated with higher levels of the specific attachment construct of proximity-seeking, but not attachment security. In addition, worse maternal psychological health was associated with attachment insecurity, but not proximity-seeking. The underlying attachment dimension of proximity-seeking may hold particular significance for mothers of adolescent daughters and may be a viable resilience target for parenting interventions.

The cortisol awakening response (CAR) is frequently assessed in psychobiological (stress) research. Obtaining reliable CAR data, however, requires careful attention to methodological detail. To promote best practice, expert consensus guidelines on the assessment of the CAR were published (Stalder et al., 2016, PNEC). However, it is unclear whether these highly cited guidelines have resulted in actual methodological improvements. To explore this, the PNEC editorial board invited the present authors to conduct a critical evaluation and update of current CAR methodology, which is reported here. (i) A quantitative evaluation of methodological quality of CAR research published in PNEC before and after the guidelines (2013-2015 vs. 2018-2020) was conducted. Disappointingly, results reveal little improvement in the implementation of central recommendations (especially objective time verification) in recent research. (ii) To enable an update of guidelines, evidence on recent developments in CAR assessment is reviewed, which mostly confirms the accuracy of the majority of the original guidelines. Moreover, recent technological advances, particularly regarding methods for the verification of awakening and sampling times, have emerged and may help to reduce costs in future research. (iii) To aid researchers and increase accessibility, an updated and streamlined version of the CAR consensus guidelines is presented. (iv) Finally, the response of the PNEC editorial board to the present results is described: potential authors of future CAR research to be published in PNEC will be required to submit a methodological checklist (based on the current guidelines) alongside their article. This will increase transparency and enable reviewers to readily assess the quality of the respective CAR data. Combined, it is hoped that these steps will assist researchers and reviewers in assuring higher quality CAR assessments in future research, thus yielding more reliable and reproducible results and helping to further advance this field of study.

The pathogenesis of Parkinson's disease (PD) is complex, multilayered, and not fully understood, resulting in a lack of effective disease-modifying treatments for this prevalent neurodegenerative condition. Symptoms of PD are heterogenous, including motor impairment as well as non-motor symptoms such as depression, cognitive impairment, and circadian disruption. Aging and stress are important risk factors for PD, leading us to explore pathways that may either accelerate or protect against cellular aging and the detrimental effects of stress. Cortisol is a much-studied hormone that can disrupt mitochondrial function and increase oxidative stress and neuroinflammation, which are recognized as key underlying disease mechanisms in PD. The more recently discovered klotho protein, considered a general aging-suppressor, has a similarly wide range of actions but in the opposite direction to cortisol: promoting mitochondrial function while reducing oxidative stress and inflammation. Both hormones also converge on pathways of vitamin D metabolism and insulin resistance, also implicated to play a role in PD. Interestingly, aging, stress and PD associate with an increase in cortisol and decrease in klotho, while physical exercise and certain genetic variations lead to a decrease in cortisol response and increased klotho. Here, we review the interrelated opposite actions of cortisol and klotho in the pathogenesis of PD. Together they impact powerful and divergent mechanisms that may go on to influence PD-related symptoms. Better understanding of these hormones in PD would facilitate the design of effective interventions that can simultaneously impact the multiple systems involved in the pathogenesis of PD.

There are known links between the hypothalamic–pituitary–adrenal (HPA) axis and systems responsible for regulating posture. Our aim was to explore directly, for the first time, whether an aspect of circadian HPA axis activity (the cortisol awakening response: CAR) was associated with greater visual dependency in postural control. For measurement of the CAR, electronically monitored saliva samples were collected by participants following morning awakening in their home environment. On the afternoons of the same days, postural sway was measured in the laboratory by exposing participants to static (control) and moving visual stimuli whilst standing still and upright on a force platform. Visual dependence was assessed as the increase in postural sway (path length) during exposure to the moving compared with the static condition. The 44 measurement days were derived from four days for each of eleven healthy participants (mean ± SD age: 51.18 ± 3.3 years). As expected, postural sway was greater when exposed to moving versus static cues. Mixed regression modelling showed that participants with smaller four day average CARs had greater deterioration in postural sway when presented with moving stimuli. These data are the first to document associations between the CAR and visual dependency in postural sway.

There is evidence that stress-induced disruption of the circadian rhythm of cortisol secretion, has negative consequences for brain health. The cortisol awakening response (CAR) is the most prominent and dynamic aspect of this rhythm. It has complex regulatory mechanisms making it distinct from the rest of the cortisol circadian rhythm, and is frequently investigated as a biomarker of stress and potential intermediary between stress and impaired brain function. Despite this, the precise function of the CAR within the healthy cortisol circadian rhythm remains poorly understood. Cortisol is a powerful hormone known to influence cognition in multiple and complex ways. Studies of the CAR and cognitive function have used varied methodological approaches which have produced similarly varied findings. The present review considers the accumulating evidence linking stress, attenuation of the CAR and reduced cognitive function, and seeks to contextualize the many findings to study populations, cognitive measures, and CAR methodologies employed. Associations between the CAR and both memory and executive functions are discussed in relation to its potential role as a neuroendocrine time of day signal that synchronizes peripheral clocks throughout the brain to enable optimum function, and recommendations for future research are provided.

The validation of accurate and meaningful assessment of cortisol in saliva samples has proved revolutionary in stress research. Its many advantages have expanded the scope of investigation from traditional laboratory and clinical settings to include multidisciplinary and community-based research. These developments have given rise to a wealth insight into the links between stress and health. Here we highlight the potential of salivary cortisol as both a product and mediator of brain function, instrumental in disturbing brain health. However, the subtleties of salivary cortisol as a measure can be underestimated, leading to misinterpretation of findings. These issues are explored, with a particular emphasis on necessary methodological rigor. Notwithstanding great promise, there is undeniably more to learn so we conclude by making recommendations for future research including use of salivary cortisol in the development of integrative predictive models of stress-related risk factors and resilience across the life course.

The cortisol awakening response (CAR) is associated with various aspects of cognition, including executive function, in older adult and clinical samples. However, the association between these variables in the healthy functioning population is not well understood due to the limited number of appropriately controlled studies. This study explored the association between the CAR and a set shifting index of executive function in 55 (44 females) healthy participants aged 20.2±3.0 years. Notoriously, assessment of the CAR from self-collected saliva samples within the domestic setting is subject to sample timing error, so electronic monitoring of both awakening and sampling times were employed. Participants attended the laboratory in the afternoon of CAR assessment for testing on the Attention Switching Task of the CANTAB neuropsychological testing battery. A positive association was found between CAR magnitude and attention-switching performance in the afternoon of the same day. This was independent of known relevant CAR covariates, but only evident in CAR data collected without delay exceeding 8 min post-awakening. These findings offer insight into a potential role for the CAR in modulating cognitive functions associated with the pre-frontal cortex.

BACKGROUND:Acute psychological stress activates the sympatho-adrenal medullary (SAM) system and hypothalamo-pituitary adrenal (HPA) axis. The relevance of this stress reactivity to long-term health and disease outcomes is of great importance. We examined prospective studies in apparently healthy adults to test the hypothesis that the magnitude of the response to acute psychological stress in healthy adults is related to future health and disease outcomes. METHODS:We searched Medline Complete, PsycINFO, CINAHL Complete and Embase up to 15 Aug 2019. Included studies were peer-reviewed, English-language, prospective studies in apparently healthy adults. The exposure was acute psychological stress reactivity (SAM system or HPA axis) at baseline. The outcome was any health or disease outcome at follow-up after ≥1 year. RESULTS:We identified 1719 papers through database searching and 1 additional paper through other sources. Forty-seven papers met our criteria including 32,866 participants (range 30-4100) with 1-23 years of follow-up. Overall, one third (32 %; 83/263) of all reported findings were significant and two thirds (68 %; 180/263) were null. With regard to the significant findings, both exaggerated (i.e. high) and blunted (i.e. low) stress reactivity of both the SAM system and the HPA axis at baseline were related to health and disease outcomes at follow-up. Exaggerated stress reactivity at baseline predicted an increase in risk factors for cardiovascular disease and decreased telomere length at follow-up. In contrast, blunted stress reactivity predicted future increased adiposity and obesity, more depression, anxiety and PTSD symptoms, greater illness frequency, musculoskeletal pain and regulatory T-Cell percentage, poorer cognitive ability, poorer self-reported health and physical disability and lower bone mass. CONCLUSION:Exaggerated and blunted SAM system and HPA axis stress reactivity predicted distinct physical and mental health and disease outcomes over time. Results from prospective studies consistently indicate stress reactivity as a predictor for future health and disease outcomes. Dysregulation of stress reactivity may represent a mechanism by which psychological stress contributes to the development of future health and disease outcomes.

The objective of this study was to determine the estrous response and the moment of ovulation and fertility after a progesterone (P4) priming plus human chorionic gonadotropin (hCG) administration in multiparous and nulliparous goats. Therefore, two experiments were conducted during non-breeding season (April and May, 26° N) and all the animals received a single injection of 20 mg of P4 and 100 IU of hCG 24 h later. In Experiment 1, 13 multiparous and 9 nulliparous goats were subjected to estrus detection twice a day from P4 administration, and their ovaries were scanned by transrectal ultrasonography every 12 h from the onset of estrus to determine ovulation. The proportion of goats in estrus did not differ between multiparous and nulliparous females. The onset of estrus (60.5 ± 12.4 h vs. 52.0 ± 5.2 h after hCG administration) and the moment of ovulation (91.5 ± 10.3 h vs. 85.3 ± 11.5 h) were also similar in multiparous and nulliparous goats. In Experiment 2, a total of 299 multiparous and nulliparous goats managed under intensive (n = 112 and 41 goats, respectively) or extensive (n = 85 and 61 goats, respectively) production systems were divided to receive a fixed-time artificial insemination (FTAI) with fresh semen at 60 or 72 h after hCG administration. The pregnancy rate did not differ significantly between multiparous and nulliparous goats in both production systems. Nonetheless, in the intensive system pregnancy rate was affected by the moment of insemination (P < 0.05). In this system, the pregnancy rate was higher in goats inseminated at 60 h than in 72 h (55.6%, 44/79 vs. 35.1%, 26/74, respectively; P < 0.05). On the contrary, in the extensive system the pregnancy rate was not affected by the time of insemination (29.4%, 23/78 vs. 22.0%, 15/68). To conclude, both the ovulatory response and the pregnancy rate after a single P4 injection plus hCG was similar between multiparous and nulliparous goats during anovulatory season. Although the pregnancy rate was not affected by the time of insemination in the extensive production system, under intensive conditions FTAI should be performed at 60 h after hCG treatment.