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Free Cortisol Levels after Awakening: A Reliable Biological Marker for the Assessment of Adrenocortical Activity

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Abstract

In three independent studies, free cortisol levels after morning awakening were repeatedly measured in children, adults and elderly subjects (total n=152). Cortisol was assessed by sampling saliva at 10 or 15 minute intervals for 30-60 minutes, beginning at the time of awakening for two days (Study 1 and 2) or one (Study 3) day, respectively. In all three studies, free cortisol levels increased by 50-75% within the first 30 minutes after awakening in both sexes on all days. Premenopausal women consistently showed a stronger increase with a delayed peak after awakening compared to men on all days. In Study 2, there was a tendency for lower early morning free cortisol levels for women taking oral contraceptives (p=.10). Stability of the area under the curve (AUC) of the early morning free cortisol levels over the three (Study 1 and 2) or two (Study 3) days ranged between r=.39 and r=.67 (p<.001). Neither age, weight, nor smoking showed an effect on baseline or peak cortisol levels. Sleep duration, time of awakening and alcohol consumption also appeared to be unrelated to early morning free cortisol levels. From these data we conclude that in contrast to single assessments at fixed times, early morning cortisol levels can be a reliable biological marker for the individual's adrenocortical activity when measured repeatedly with strict reference to the time of awakening.

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... Meanwhile, cortisol secretion also follows a circadian rhythm [15]; cortisol levels in serum and saliva robustly increase and reach a circadian peak within the first hour after morning awakening from nocturnal sleep in men and women of all ages [16,17]. this phenomenon is called the cortisol awakening response (caR), resulting from the suprachiasmatic nucleus (scN)-mediated activation of the hypothalamic-pituitary-adrenal (hPa) axis [18,19]. ...
... in healthy individuals, the caR emerges within the first hour after the morning awakening from nocturnal sleep [16]; however, it is not observed after waking in the night or after a nap in the early evening [28,29]. typical caR is defined as an increase in cortisol level to at least 2.5 nmol/l above an individual's baseline in healthy individuals, that is, a net increase of cortisol levels (caRi): cortisol levels at 30 min post-awakening -cortisol levels immediately upon awakening) ≥ 2.5 nmol/l [30]. ...
... these results are similar to a previous study that demonstrated a significant negative correlation between age and caRi and caRauc levels [55]. however, our results are inconsistent with the findings of two other studies that showed no significant effect of age on caR [16,30]. the age-related concomitant decrease in testosterone and cortisol levels during the post-awakening period suggests the potential effect of age-related functional changes in the scN because of the decline in the number of ViP-producing neurons after 40 years of age [56]. ...
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Background The lack of association between serum testosterone levels and symptoms suggestive of hypogonadism is a significant barrier in the determination of late-onset hypogonadism (LOH) in men. This study explored whether testosterone levels increase after morning awakening, likewise the cortisol awakening response (CAR) in the hypothalamic–pituitary–adrenal (HPA) axis, and whether testosterone levels during the post-awakening period are associated with age and symptoms suggestive of late-onset hypogonadism (LOH) in men. Methods Testosterone and cortisol levels were determined in saliva samples collected immediately upon awakening and 30 and 60 min after awakening, and scores of the Aging Males’ Symptoms (AMS) questionnaire were obtained from 225 healthy adult men. Results A typical CAR (an increase in cortisol level ≥ 2.5 nmol/L above individual baseline) was observed in 155 participants (the subgroup exhibiting typical CAR). In the subgroup exhibiting CAR, testosterone levels sharply increased during the post-awakening period, showing a significant negative correlation with age, total AMS score, and the scores of 11 items on the somatic, psychological, and sexual AMS subscales. Of these items, three sexual items (AMS items #15–17) were correlated with age. Meanwhile, there was no notable increase in testosterone levels and no significant correlation of testosterone levels with age and AMS score in the subgroup exhibiting no typical CAR (n = 70). Conclusions The results indicate that the hypothalamus-pituitary-gonad (HPG) axis responds to morning awakening, and determining testosterone levels during the post-awakening period in men with typical CAR may be useful for assessing HPG axis function and LOH.
... In sport, the cortisol awakening response (CAR) has garnered interest to evaluate the physical and/or psychological effects of training and competition [1]. The CAR is a distinct and reliable feature of hypothalamic-pituitary-adrenal (HPA) activity, characterized by a cortisol surge that peaks around 30-45 mins after awakening [2]. Contemporary viewpoints position the CAR as a proxy for baseline stress [3], reflecting both prior stress experienced and stress anticipation. ...
... Following an overnight (> 8 hours) fast, capillary blood samples were collected at three post-awakening points (+3, +30, +60 mins) for CAR and TAR determination. This 3-point protocol was chosen to capture the peak awakening surge (~30-45 mins) in cortisol [2,30]. ...
... After the light training block, plasma cortisol values rose by 36% (+30 mins) and 22% (+60 mins) over waking levels, whilst plasma testosterone values decreased by -11% and -15% at these time points, consistent with general findings in athletic [4,5,7,8,17,18,33] and non-athletic men [2,15,16,34,39]. Training intensity appears to play a regulatory role with a heavy training block suppressing the CAR (21% and 8% increases) and attenuating the TAR (-7% and -13% decreases), respectively. ...
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In sport, the awakening responses of cortisol (CAR) and testosterone (TAR) have been used as evaluative tools. Research findings are, however, inconsistent and the mechanisms involved are unclear. This study investigated the CAR and TAR in male athletes across light and heavy training weeks, focusing on skeletal muscle damage as a mediating factor. Twenty elite male judokas were assessed across consecutive weeks of light and heavy training (i.e., 6 days, 9-10 weekly sessions). Plasma cortisol and testosterone concentrations were measured post-awakening (+3, +30, +60 mins), along with creatine kinase (CK) at +3 mins. The CAR and TAR were indexed by baseline-corrected change scores (Δb30, Δb60) and area under the curve (AUCb30, AUCb60). The early-morning surge in plasma cortisol concentration (CARΔb30, CARΔb60, CARAUCb30, CARAUCb60) was significantly larger after light versus heavy training with effect-size differences of 2.14-2.64. The post-awakening decline in plasma testosterone (TARΔb30, TARAUCb30, TARAUCb60) was found to be significantly less pronounced, whilst CK level was elevated, after heavy than light training with effect-size differences of 0.95-1.04 and 4.70, respectively. Causal mediation analysis confirmed that CK mediated, in part, the training effect on the CAR, but not TAR, measures. In summary, male judokas, upon rising after a light training block, displayed a rising CAR (36%, 22%) and declining TAR (-11%, -15%) at +30 and +60 mins. A high-intensity training block suppressed the CAR (21%, 8%) and attenuated the TAR (-7%, -13%) with accompanying muscle damage offering one mechanism to partly explain the CAR differences.
... Almost exclusively measured in saliva [4], it is claimed that the CAR is a distinct phenomenon superimposed upon the circadian rhythm of cortisol [5,6] and an ancient adaptive feature preparing the body in anticipation of the energy needs for the day ahead [7,8] The CAR has attracted a lot of interest and is now a widely accepted term in the field of psychoneuroendocrinology. It is cited as a reliable measure of adrenocortical activity [9], which has led to its common use as a biomarker of stress reactivity and HPA functionality [10,11]. Compared with healthy controls, altered CAR patterns are reported for Cushing's [12], chronic fatigue [13], depression and psychosis [14,15], post-traumatic stress disorder [16] and obesity [17]. ...
... While there are numerous examples of studies demonstrating cortisol increase in the period after waking (for example [9,25], which are commonly cited to support the existence of a CAR), we found that there are very few studies that specifically examine pre-and post-waking cortisol. In 1992, Späth-Schwalbe et al. [25] measured cortisol before and after awakening in a small cohort (14 healthy men, aged 20−34). ...
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Cortisol is released upon activation of the hypothalamic–pituitary–adrenal axis, varies across the day, possesses an underlying diurnal rhythm and is responsive to stressors. The endogenous circadian peak of cortisol occurs in the morning, and increases in cortisol observed post-awakening have been named the cortisol awakening response (CAR) based on the belief that the act of waking up stimulates cortisol secretion. However, objective evidence that awakening induces cortisol secretion is limited. We used a mixed effects model with a linear spline fitted to the data to examine tissue-free cortisol measurements obtained from 201 healthy volunteers by automated ambulatory microdialysis before and after awakening in their home environments. We also examined rate of change of cortisol depending on sleep duration and relative timing. We found no evidence for a change in the rate of cortisol increase in the hour after waking when compared with the hour prior to waking. We instead observed substantial interindividual variability in the absolute concentration and rate of change of cortisol levels, and differences in dynamics that may be attributable to duration and relative timing of sleep. Based on these results, we strongly suggest caution is needed when interpreting cortisol measurements solely obtained in the hour after waking.
... Another way to assess HPA axis activity (via salivary cortisol) is by measuring cortisol within the first 60 min after waking up, i.e., the cortisol awakening response (CAR) [93]. ...
... This parameter combines the characteristics of a reactivity index (awakening response) with aspects related to circadian regulation (occurring at approximately the same time every 24 h); therefore, the CAR represents a strong increase in cortisol levels during the first 30 to 45 min after morning awakening [93,94]. ...
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Background: Numerous studies have evaluated the effect that mindfulness-based interventions (MBIs) have on multiple health outcomes. For its part, stress is a natural response to environmental disturbances and within the associated metabolic responses, alterations in cortisol levels and their measurement in different tissues are a way to determine the stress state of an individual. Therefore, it has been proposed that MBIs can modify cortisol levels. Methods and results: The objective of this systematic review was to analyze and summarize the different studies that have evaluated the effect of MBIs on cortisol levels. The following databases were consulted: MEDLINE, AMED, CINAHL, Web of Science, Science Direct, PsycINFO, SocINDEX, PubMed, the Cochrane Library and Scopus. The search terms “mindfulness”, “mindfulness-based interventions” and “cortisol” were used (and the search was limited to studies from January 1990 to May 2024). In order to reduce selection bias, each article was scrutinized using the JBI Critical Appraisal Checklist independently by two authors. We included those studies with specified intervention groups with at least one control group and excluded duplicate studies or those in which the intervention or control group was not adequately specified. Significant changes in cortisol following MBIs were found in 25 studies, while 10 found no changes. The small sample size, lack of randomization, blinding, and probable confounding and interaction variables stand out in these studies. Conclusion: MBIs have biological plausibility as a means of explaining a positive effect on cortisol levels; however, the weakness of the studies and the absence of robust designs makes it difficult to establish a causal association between both variables. Registration number: INPLASY2024110017.
... It is a neuroendocrine manifestation of the HPA axis to face anticipated stress (Chida & Steptoe, 2009). Cortisol increases sharply during the first 30-45 min after waking, peaks and then declines throughout the day (Pruessner et al., 1997). In healthy adults, an increase of 50-156% in cortisol is typically seen after waking (Clow et al., 2004;Pruessner et al., 1997). ...
... Cortisol increases sharply during the first 30-45 min after waking, peaks and then declines throughout the day (Pruessner et al., 1997). In healthy adults, an increase of 50-156% in cortisol is typically seen after waking (Clow et al., 2004;Pruessner et al., 1997). These increases are a normal adaptive neuroendocrine process. ...
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The social identity model of identity change (SIMIC) posits that social group memberships protect well‐being during transitional periods, such as the transition to university, via two pathways — maintaining previously held social group memberships (social identity continuity) and gaining new social group memberships (social identity gain). Breaking new ground, this study investigates how these processes can influence an important biomarker of stress — cortisol awakening response (CAR). A total of 153 first year undergraduate students (69.3% female) completed measures (group memberships, depression, life satisfaction) at the beginning of the academic year (October, time 1; T1), of which 67 provided a saliva sample for CAR assessment. Seventy‐nine students completed the time 2 (February, T2) measures 4 months later (41 provided saliva). Academic performance was assessed objectively through end‐of‐academic year university grade data (June, T3). At T1, students who maintained and gained social group memberships reported lower depressive symptoms and greater life satisfaction. Across the academic year, social identity gain was associated with a larger post‐awakening cortisol response at T2, indicative of a better ability to cope with stress. Thus, gaining new social group memberships during the transition to university was associated with a better ability to cope with stress.
... The findings support the idea that emotional stress is one of the etiological components of bruxism and show a positive connection between bruxism and urine catecholamine levels. [12] The most popular method of measuring an individual's stress level is to measure the amount of cortisol secreted by the hypothalamus, which was initially established by Pruessner et al. (1997). The results of this study indicating stress as an etiological factor for bruxism may be related to the level of salivary cortisol upon waking, which is linked to chronic stress. ...
... The results of this study indicating stress as an etiological factor for bruxism may be related to the level of salivary cortisol upon waking, which is linked to chronic stress. [13] A cross-sectional study was carried out by Pontes and Prietsch (2019) on a sample of 1280 urban residents who were 18 years of age or older. The authors evaluated the frequency of sleep bruxism, its primary indications and symptoms, and the relationship between bruxism and psychological stress. ...
Article
Bruxism is an issue that has a major influence on both dental and general health. It is defined by the involuntary clenching and grinding of the teeth. Bruxism can present itself in two main ways: during sleep and during wakefulness. This study investigates the function of the stress hormone cortisol in the development and treatment of bruxism. Those who have bruxism often have elevated cortisol levels, which suggests a strong correlation between stress and bruxism episodes. The study examines the body of research, emphasizing the link between bruxism and hormone changes brought on by stress. It also looks at possible cortisol-management-based therapeutic approaches. Pharmacological therapy, lifestyle adjustments, and stress management strategies are examples of effective interventions. Comprehending the intricate relationship between bruxism and cortisol will aid medical professionals in creating all-encompassing therapy strategies that can ultimately enhance patient results and quality of life.
... Only a limited number of studies have employed such approaches, and not all of them have reported sex differences, as endogenous circadian melatonin and CBT rhythms often take precedence as primary circadian endpoints in these studies. The few studies that did measure CAR levels report mixed results, with some suggesting a more robust and sustained (~25 min) increase in cortisol levels after waking in females [71][72][73][74], while other studies do not observe these differences [75,76]. Crucially, studies noting sex differences in the CAR indicate minimal effect sizes, with sex accounting for only 1-3% of the observed variability [71,72,77]. ...
... The few studies that did measure CAR levels report mixed results, with some suggesting a more robust and sustained (~25 min) increase in cortisol levels after waking in females [71][72][73][74], while other studies do not observe these differences [75,76]. Crucially, studies noting sex differences in the CAR indicate minimal effect sizes, with sex accounting for only 1-3% of the observed variability [71,72,77]. While previous studies suggested an increased CAR during ovulation or an attenuated CAR during menses, more recent ones indicated no effect of the menstrual phase on the CAR [78][79][80]. ...
... Key brain regions involved in memory formation, such as the hippocampus and amygdala, do not receive direct projections from the SCN. Instead, they are influenced by circadian regulation through intermediary pathways or hormonal signaling [24,28]. ...
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Circadian rhythms influence memory formation, consolidation, and retrieval. The suprachiasmatic nucleus coordinates the internal circadian timing with external environmental signals, serve as the central pacemaker. This alignment influences the timing and efficiency of synaptic plasticity across various brain regions, particularly the hippocampus. Normal circadian regulation affects hippocampus-dependent processes such as long-term depression and long-term potentiation, contributing to time-of-day variations in memory consolidation. These activities are governed by core clock genes, which interact with signaling pathways like the cAMP-MAPK-CREB cascade. Additionally, circadian rhythms are modulated by hormones such as cortisol and melatonin, which help regulate sleep cycles and memory processing. Sleep deprivation or disruptions in circadian rhythms, like irregular light exposure, can impair cognitive function and hinder memory performance. Understanding the mechanisms linking circadian rhythms and memory could provide new treatment approaches for memory dysfunctions associated with disrupted circadian control.
... Chronic stressful situations can predispose one to an imbalance in its homeostasis [28]. Cortisol levels show distinct diurnal variations related to the sleep-wake cycle, peaking shortly after waking up and gradually decreasing to their lowest levels around midnight [29]. Bailey et al. conducted a study involving 19 healthy adults, with 10 identifying as the MC and 9 as the EC. ...
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The chronotype, the personal predisposition towards morning or evening activities, significantly influences health conditions, sleep, and eating regulations. Individuals with evening chronotypes are often at a higher risk for weight gain due to misalignment between their natural tendencies of functioning and social schedules, resulting in insufficient sleep, disruptions in eating habits, and decreased physical activity levels. Often, impaired glucose tolerance and changes in melatonin, adiponectin, and leptin secretion, along with alterations in the clock gene functions in subjects with evening preferences, may be predisposed to obesity. These disturbances contribute to metabolic dysregulation, which may lead to the subsequent onset of obesity complications, such as hypertension, type 2 diabetes, sleep apnea, and liver diseases. Targeting critical components of the circadian system and synchronizing people’s chronotypes with lifestyle conditions could deliver potential strategies for preventing and treating metabolic disorders. Thus, it is recommended to take a personalized chronobiological approach to maintain a normal body weight and metabolic health. Nevertheless, future studies are needed to identify the clear mechanisms between the chronotype and human health. This article provides a narrative review and discussion of recent data to summarize studies on the circadian rhythm in the context of obesity. The manuscript represents a comprehensive overview conducted between August and November 2024 using the National Library of Medicine browser (Medline, Pub-Med, Web of Science).
... 皮质醇觉醒反应(Cortisol Awakening Response, CAR)作为应激激素皮质醇昼夜节律活动的一部分, 它是指个体的皮质醇水平在觉醒后的 30~45 分钟内 出现峰值, 并且在 1 小时内增加 50%至 160%(Clow et al., 2004;Pruessner et al., 1997)。由于了解 CAR ...
... Salivary cortisol levels are superimposed on the circadian rhythm, with morning cortisol levels reaching as high as 27.3 ng/mL before declining throughout the day 6,7 . This independent phenomenon is known as the cortisol awakening response, comprising of an increase in cortisol peak values by at least 50% within 30 min post-awakening 8,9 . www.nature.com/scientificreports/ ...
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Traditional methods for management of mental illnesses in the post-pandemic setting can be inaccessible for many individuals due to a multitude of reasons, including financial stresses and anxieties surrounding face-to-face interventions. The use of a point-of-care tool for self-management of stress levels and mental health status is the natural trajectory towards creating solutions for one of the primary contributors to the global burden of disease. Notably, cortisol is the main stress hormone and a key logical indicator of hypothalamic-pituitary adrenal (HPA) axis activity that governs the activation of the human stress system. Therefore, the measurement of cortisol is imperative to lead the discussion of the relationship between psychological stress and mental health deterioration. The aim of the current study was to determine salivary cortisol concentrations of healthy individuals undergoing the MAST protocol for human stress activation, through optical-colorimetric techniques. The study demonstrates the use of the blue tetrazolium (BT) method as successful means of rapid measurement of cortisol in saliva, comparable to the gold-standard technique i.e., enzyme-linked immunoassays (ELISA) with a coefficient of determination (R²) of 0.997. The results support the future development of a point-of-care optical sensor-based device and mobile application for cortisol monitoring and stress profiling in adults.
... A systematic review pointed out that in 45% of the studies explored, people with epilepsy had higher basal cortisol levels than healthy people [3]. Nevertheless, some discrepancies were also found, probably due to methodological aspects, such as the variability and sample size, the different types of specimens used to collect cortisol, or the moment of the day in which cortisol was gathered [3,14]. ...
... After wakening, blood cortisol reaches its peak level after 30-45 min, known as the Cortisol Awakening Response (CAR). Following the CAR, cortisol levels gradually decrease throughout the day, reaching the lowest levels near bedtime, a process known as the diurnal cortisol slope (DCS) (Pruessner et al. 1997). However, under stress-induced situations, waves of GC secretion occur on top of diurnal fluctuations that can lead to HPA dysregulation and may be associated with detrimental mental health effects (De Kloet and Joels 2023). ...
... The cortisol awakening response is a key component of the daily circadian cortisol rhythm. Normal CAR increases one's cortisol levels within the first hour of waking up and declines throughout the rest of the day [85,86,87]. Chronic stress has shown to change the CAR in a bi-directional way. ...
... As the end-product of the HPA axis, most research has focused on cortisol, largely through saliva samples but less commonly via blood (serum), hair, or urine [24]. Cortisol levels often increase in response to a stressor [25], and tend to follow a diurnal pattern in which they steadily increase in the second half of the night, peak shortly after waking (i.e., within 30 to 60 minutes), and then gradually decrease across the day [26]. Due to this diurnal rhythm, and the fact that cortisol levels are affected by many factors (e.g., diet, sleep) [27], there are complexities in measuring it, and various approaches have been used including collecting single (e.g., pre-work) or multiple (e.g., cortisol awakening response) morning samples, and samples taken serially across the day (e.g., afternoon, evening) [21]. ...
Article
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Burnout is a growing problem in high-performance sport and has negative consequences for athletes (e.g., mental ill-health). It is therefore important to effectively monitor athlete burnout to aid intervention efforts. While self-report measures are available (e.g., athlete burnout questionnaire), the limitations associated with these measures (e.g., social desirability bias) means that objective physiological markers may also be useful. Thus, this article critically discusses potential biomarkers of athlete burnout, drawing on research inside and outside of sport to offer an overview of the current state-of-the-art in this research area. First, it outlines what athlete burnout is, its deleterious consequences, and discusses existing psychological assessments. The article then critically discusses literature on hypothalamic-pituitary-adrenal axis (e.g., salivary cortisol) and autonomic nervous system (e.g., heart rate variability) indices of burnout, highlighting some promising biomarkers for future research (e.g., salivary cortisol at bedtime, vagally-mediated heart rate variability at rest). Finally, the article concludes by highlighting key considerations and offering recommendations for future research (e.g., use of more homogenous methods in assessing burnout and physiological parameters). As a result, the intention of this article is to spark more higher quality research on the psychophysiology of athlete burnout, thereby helping tackle this prominent issue in high-performance sport.
... Inversely, cortisol levels increased after waking, declined over the day, and increased in the evening. This association emerged for quadratic and cubic trends, which is expected given the nonlinear nature of diurnal AA and cortisol levels (Adam and Kumari 2009;Nater et al. 2006;Pruessner et al. 1997). ...
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Research and theory suggest an important role of neuroendocrine function in emotional development, particularly under conditions of elevated stress. We provide empirical data to clarify associations between alpha-amylase (AA) and cortisol as well as test the differential linkages among AA, cortisol, and symptoms of anxiety, depression, and posttraumatic stress in children. Children recruited from a low-income elevated violence community (n = 100; mean age = 10, SD = 0.64; 79% Latino; 67% received free or reduced lunch) were assessed on diurnal levels of AA and cortisol along with assessments of anxiety, depression, and posttraumatic stress symptoms (PTSS). Elevated anxiety symptoms were associated with steeper linear slopes of AA with higher levels of AA in the morning but lower levels of AA in the evening. Depression was associated with differential cubic trajectories of AA when PTSSs were included in the model. Anxiety also predicted differential cubic diurnal trends in cortisol, such that greater anxiety symptoms were associated with relatively higher levels of cortisol in the evening. Again, depression symptoms when PTSS were included predicted diurnal cubic trends with elevated depression associated with lower awakening and midday cortisol that reversed to higher evening cortisol compared to youth with fewer self-reported depression symptoms.
... Further, a single daily measurement of saliva was opted for, a decision driven by practical and financial constraints. While a single sample in the morning is often and reliably used to assess diurnal secretory activity to assess within-subject variations over a certain period in an older population [98], this approach does not comprehensively reflect the intricate diurnal fluctuations of cortisol nor account for inter-individual day-to-day and intra-individual variations, especially within a smaller sample [99,100]. Future studies could integrate multiple measurements across consecutive days to gain a more nuanced understanding of cortisol dynamics and its relationship with DHEA [101]. ...
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Background Low physical activity among older adults is related to adverse health outcomes such as depression and loneliness, poor physical function and increased risk of falls. This study was designed to increase physical activity through a digital, group-based, physical activity and music intervention and to examine its effectiveness on social, mental and physical health outcomes. Methods Participants were 34 older adults (65 years +) recruited across four care homes in Scotland to a pilot study. Surveys were administered at baseline and post-intervention, comprising measures of fear of falling, depression and anxiety, loneliness, sleep satisfaction and quality of life. A battery of physical function tests and saliva sampling for cortisol and dehydroepiandrosterone hormone analysis were also conducted at each time point. Additionally, process evaluation measures (recruitment, intervention fidelity, attendance, retention rates and safety) were monitored. The intervention comprised 12 weeks of three prescribed digital sessions per week: movement and music (n = 2) and music-only (n = 1), delivered by an activity coordinator in the care home. Post-intervention interviews with staff and participants were conducted to gain qualitative data on the acceptability of the intervention. Results An average of 88% of prescribed sessions were delivered. Pre- to post-intervention intention-to-treat analysis across all participants revealed significant improvements in anxiety, salivary DHEA, fear of falling and loneliness. There were no significant improvements in health-related quality of life, perceived stress, sleep satisfaction or physical function tests, including handgrip strength. Qualitative analysis highlighted benefits of and barriers to the programme. Conclusions The digital movement and music intervention was deemed acceptable and delivered with moderate fidelity, justifying progression to a full-scale trial. Although a proper control group would have yielded more confident causal relationships, preliminary psychosocial and biological effects were evident from this trial. To show significant improvements in physical function, it is likely that a bigger sample size providing sufficient power to detect significant changes, greater adherence, longer intervention and/or higher exercise volume may be necessary. Trial registration The trial is registered at ClinicalTrials.gov, number NCT05601102 on 01/11/2022.
... The diurnal cortisol slope, which represents the gradual drop in cortisol levels throughout the day, and the cortisol awakening response (CAR), which peaks soon after waking, are the two distinct components of the cortisol production pattern that occurs throughout the day [43][44][45][46]. Since cortisol is essential for the regulation of many biological systems, such as the immunological, inflammatory, and metabolic processes, irregularities in its circadian rhythm can have long-term negative effects on these systems as well as general health [47][48]. ...
... Mothers' Cortisol: Prior to 21 weeks' gestation, diurnal suites of salivary cortisol were collected over two days from mothers. Samples were used to calculate the area under the curve ground (AUCg) cortisol estimates, adjusted for waking times, as is considered best practice [80,81]. We also calculated the area under the curve increase (AUCi) cortisol estimates from waking and 30 min post-waking cortisol data points, reflecting the increase in cortisol in the morning [82,83]. ...
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Insecure and disorganized attachment patterns in children are linked to poor health outcomes over the lifespan. Attachment patterns may be predicted by variables that influence the quality of children’s interactions with their primary caregivers/parents (usually mothers) such as prenatal and postnatal exposures and the children’s own behaviours in interactions. The purposes of this exploratory study were to examine: (1) prenatal predictors of children’s attachment patterns, and (2) postnatal mediators and moderators of associations between prenatal predictors and children’s attachment patterns, with adjustment for relevant covariates. Mother–child dyads (n = 214) from the longitudinal Alberta Pregnancy Outcomes and Nutrition (APrON) cohort were studied using valid and reliable measures. Hayes’ mediation analysis was employed to determine direct and indirect effects. Mothers’ prenatal cortisol levels directly predicted disorganized (versus organized) child attachment in unadjusted models. Children’s passivity (in adjusted models) and compulsivity (in unadjusted and adjusted models) in parent-child interactions mediated the pathway between mothers’ prenatal cortisol levels and children’s disorganized attachment patterns. Serial mediation analyses revealed that mothers’ cortisol levels predicted their children’s cortisol levels, which predicted children’s compulsivity, and, ultimately, disorganized attachment in both unadjusted and adjusted models. No predictors were correlated with children’s insecure (versus secure) attachment. This exploratory research suggests that prenatal exposure to mothers’ cortisol levels and children’s behavioural contributions to parent–child interaction quality should be considered in the genesis of children’s attachment patterns, especially disorganization. Interventions focused on parent-child interactions could also focus on addressing children’s behavioral contributions.
... application (56)(57)(58). Elevated cortisol secretion or its misalignment with normal circadian rhythms could potentially disrupt the restactivity circadian rhythm and negatively affect sleep quality (59,60). ...
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Background In modern society, achieving high-quality sleep is increasingly challenging. We conducted a study to explore the potential benefits of daytime physical activity and balneotherapy, including mud application and thermal-water bathing, on sleep quality. Methods To assess daytime physical activity and sleep parameters, we actigraphically monitored 127 healthy participants (34.6% male, average age 64.61 ± 0.89 years) during a one-week stay at a spa resort, where they received mud application and thermal-water bathings. Results Participants were divided into three groups based on the timing of mud application. Those receiving mud application before 8:30 a.m. tended to have shorter sleep durations compared to those with later application, especially if it occurred before 7:45 a.m. However, mud application did not significantly affect sleep quality. Three-way ANCOVA revealed a significant effect of daytime physical activity on delta Sleep Efficiency, but post-hoc tests were insignificant. Furthermore, analyzing the duration of daily thermal-water bathings, individuals bathing for over 75 min per day experienced a noteworthy improvement in sleep quality, particularly in terms of delta Sleep Efficiency (2.15 ± 0.9% vs. −0.34 ± 0.31%, p = 0.007). Conclusion Our findings suggest that extended thermal-water bathing may enhance objective aspects of sleep quality. Since balneotherapy is mainly prescribed for individuals with musculoskeletal pathologies or psychological disorders, these findings may encourage doctors to recommend bathing in thermal water also to healthy subjects. Future researchers need to investigate the role of daytime physical activity in depth.
... 9,10 In addition, the cortisol awakening response, observed within the first hour after waking, is a well-documented phenomenon associated with various psychosocial factors, such as depression and anxiety disorders. 11,12 HRV reflects the time intervals between successive heartbeats. 13 Studies in psychology and neuroscience confirm that HRV measurements mirror the dynamic interplay between the sympathetic and parasympathetic branches of the autonomic nervous system, essential for maintaining physiological arousal homeostasis. ...
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Stressful situations lead to change in or damage to the central nervous system, the hypothalamic-pituitary-adrenal axis, and autonomic function. Techniques for reducing stress such as yoga and mindfulness meditation have been reported to improve emotional regulation and mindfulness skill, as well as stress response. Mindfulness skill relies on intense focus to quiet the mind and bring concentration to the present moment. The present study was a randomized control trial to investigate the effects of an 8-week training program (three 45-minute sessions/week, one session with an instructor and two sessions as home practice) in mindfulness meditation or in yoga on stress and related variables in healthy people. Forty-four healthy participants were randomly allocated to one of three groups: a mindfulness group (n = 16), a yoga group (n = 13), and a control group (n = 15). The yoga training significantly modified heart rate variability, contributing to decreased relative power of the low-frequency band; the relative power of the high-frequency band increased after training. The mindfulness meditation training significantly improved mindfulness skill and concentration performance. In the present study, yoga was associated with increased heart rate variability and mindfulness meditation was associated with an increase in mindfulness skill and concentration performance.
... Cortisol secretion is regulated by the circadian rhythm, which is influenced by external cues called zeitgebers, such as light-dark cycle, [5,6] awakening [7] and social cues. [8] Light, in particular, plays a crucial role in the entrainment of the circadian rhythm. ...
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Introduction Cortisol secretion is regulated by circadian rhythm, which is influenced by zeitgebers like light. In India, the entire country operates under a single time zone, Indian Standard Time, which may not align with the local sunrise timing across different regions. Aims This study aimed to compare the basal serum cortisol levels between 06:00 AM and 09:00 AM in Guwahati, Assam, where sunrise occurs earlier compared with the western part of the country. A cross-sectional pilot study was conducted from December 2022 to June 2023 in a tertiary care hospital in Guwahati. Methods Serum cortisol samples were collected at 06:00 AM and 09:00 AM from 25 healthy adult participants once in winter and again in summer. Descriptive statistics and paired Student’s t-tests were used. Results The mean serum cortisol levels at 06:00 AM in winter, summer and overall were 13.2, 13.4 and 13.3 μg/dL, respectively. At 09:00 AM, the mean serum cortisol levels in winter, summer and overall were 8.2, 7.7 and 8.0 μg/dL, respectively. Significant differences were observed between the 06:00 AM and 09:00 AM cortisol levels in both winter and summer ( P <0.001). Conclusion This study highlights the importance of considering the influence of earlier sunrise on circadian rhythm, cortisol secretion and sampling protocols. Recognising the impact of earlier sunrise on cortisol secretion and adapting sampling protocols accordingly to align with the local sunrise can provide a more accurate assessment of basal cortisol levels and help avoid potential misinterpretation and diagnostic challenges associated with low values.
... From a systems level it is known that GC's play an important role in entraining the circadian system. GC's themselves feature circadian fluctuations in expression, and are generally highest immediately prior to awakening, and then gradually decrease until the next period of awakening (Oster et al., 2016;Pruessner et al., 1997). Furthermore, chronic and sub-acute post-natal physical and social stress have been demonstrated to cause a phase advance in PER2 adrenal and pituitary clock rhythms of adult mice, alongside tissue specific peripheral circadian clock shifts. ...
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The embryonic environment is critical in shaping developmental trajectories and consequently post-natal phenotypes. Exposure to elevated stress hormones during this developmental stage is known to alter a variety of post-natal phenotypic traits, and it has been suggested that pre-natal stress can have long term effects on the circadian rhythm of glucocorticoid hormone production. Despite the importance of the circadian system, the potential impact of developmental glucocorticoid exposure on circadian clock genes, has not yet been fully explored. Here, we showed that pre-natal exposure to corticosterone (CORT, a key glucocorticoid) resulted in a significant upregulation of two key hypothalamic circadian clock genes during the embryonic period in the Japanese quail (Coturnix japonica). Altered expression was still present 10 days into post-natal life for both genes, but then disappeared by post-natal day 28. At post-natal day 28, however, diel rhythms of eating and resting were influenced by exposure to pre-natal CORT. Males exposed to pre-natal CORT featured an earlier acrophase, alongside spending a higher proportion of time feeding. Females exposed to pre-natal CORT featured a less pronounced shift in acrophase and spent less time eating. Both males and females exposed to pre-natal CORT spent less time inactive during the day. Pre-natal CORT males appeared to feature a delay in peak activity levels. Our novel data suggest that these circadian clock genes and aspects of diurnal behaviours are highly susceptible to glucocorticoid disruption during embryonic development, and these effects are persistent across developmental stages, at least into early post-natal life.
... Cortisol is the end product of the HPA axis and displays the same circadian rhythm [17]. Its levels experience a rapid increase in the first 30-40 min of awakening, reaching a peak known as the cortisol awakening response; subsequently, the level gradually declines throughout the day until reaching the nadir at midnight [18][19][20], during which time the HPA axis activity is also at its minimum [17]. Therefore, this level has a wide range. ...
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Acute sleep deprivation has aroused widespread concern and the relationship between acute sleep deprivation and cortisol levels is inconsistent. This study aimed to explore additional evidence and details. The PubMed, Web of Science, EMBASE, CLINAHL and Cochrane databases were searched for eligible studies published up to June 7, 2023. All analyses were performed using Review Manager 5.4 and Stata/SE 14.0. A total of 24 studies contributed to this meta-analysis. There was no significant difference in cortisol levels between participants with acute sleep deprivation and normal sleep in 21 crossover-designed studies (SMD = 0.18; 95% CI: –0.11, 0.45; p = 0.208) or 3 RCTs (SMD = 0.26; 95% CI: –0.22, 0.73; p = 0.286). Subgroup analysis revealed that the pooled effects were significant for studies using serum as the sample (SMD = 0.46; 95%CI: 0.11, 0.81; p = 0.011). Studies reporting cortisol levels in the morning, in the afternoon and in the evening did not show significant difference (p > 0.05). The pooled effects were statistically significant for studies with multiple measurements (SMD = 0.28; 95%CI: 0.03, 0.53; p = 0.027) but not for studies with single cortisol assessments (p = 0.777). When the serum was used as the test sample, the cortisol levels of individuals after acute sleep deprivation were higher than those with normal sleep.
... Since its initial systematic description 20 years ago by Pruessner, the CAR has attracted considerable interest in stress-related research due to its potential role in preparing the individual to deal with the upcoming daily demands. Both heightened and blunted CARs have been related to psychosocial stress and poor health outcomes [3]. Besides CAR, the two other most commonly employed measures of cortisol in largescale, epidemiological research, are diurnal cortisol slope (i.e., the degree of cortisol decline from early morning to late evening), and the area under the daytime cortisol curve (i.e., the area under all the cortisol data points measured across the waking day) [4]. ...
Article
Objectives There is a growing interest in the relevance of salivary cortisol and cortisone concentrations in stress-related research. To correctly attribute the magnitude of salivary cortisol and cortisone variation as an effect of a stressful event, a coherent understanding of the day-to-day intra-individual and inter-individual variability across the diurnal cycle of the two steroids is required. However, such information is currently lacking. Methods This study aimed to overcome these existing limitations by performing an investigation of the biological variation (BV) of salivary cortisol and cortisone within one day and between five days using an LC-MS/MS method. Saliva samples were collected from 20 healthy volunteers immediately after waking up, at 8:00, 12:00, 15:00, 19:00 and 23:00 on each day over five days. All samples were analyzed in duplicate in one run. Nested ANOVA was used to calculate the sums of squares for analytical and biological components of variation. Results The within-subject BV of salivary cortisol and cortisone (CV I ) ranged from a minimum of 29.3 and 19.0 % to a maximum of 56.5 and 49.1 %, respectively, while the between-subject biological variation (CV G ) ranged from 29.7 and 29.0 % to 51.6 and 43.6 %. The reference change values (RCVs) ranged from 96 to 245 % for cortisol and from 55 to 194 % for cortisone. A medium index of individuality was observed for both compounds at all time points. Conclusions This study provides updated BV estimates and RCVs for different times of day that can be used to assess the magnitude of change in biomarkers in future stress-related research.
... Cortisol secretion is affected by the circadian rhythm, with the lowest fluctuations expected in the late afternoon and the highest concentrations of cortisol expected in the morning between 7 and 10 a.m. (The specific time a person wakes has no major influence on the morning cortisol response, and within 30 min after waking, the free cortisol level rises from 50% to 75%.) [15]. Salivary cortisol values are affected by a number of factors, including during the body's response to stress: Age and gender, endogenous and exogenous sex hormone values (e.g., menstrual cycle, oral contraceptive use, hormone replacement therapy, pregnancy, breastfeeding), certain medications (psychopharmaceuticals, corticosteroids), smoking, energy-rich diets, coffee and alcohol consumption, and exercise [16]. ...
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Academic stress affects students’ psychological and physiological well-being. Dental undergraduate programs are known for their demanding curriculum, leading to significant stress symptoms. The objective was to determine if salivary cortisol levels were higher in students exposed to academic stress, assess the relationship between stress severity/temperament and cortisol values, and explore relaxation technique effects. Salivary cortisol was measured at two time points for all participants: Before exams and during a relaxation period after summer break. A third measurement was conducted for students with high pre-test cortisol levels who received instructions on progressive muscle relaxation (PMR) before subsequent exams. Additionally, participants completed two questionnaires: Perceived Stress Scale (PSS) and Fisher’s Temperament Questionnaire. The group analysis based on the PSS indicated that 39 participants reported high stress. Women demonstrated significantly higher stress than men (p = 0.042054). A significant difference in stress levels was observed between director and builder temperament types (p = 0.029276). Cortisol levels showed a significant decrease from the first measurement to the second measurement, and the third measurement after implementing PMR. The grade in the “Dermatovenereology” course correlated with stress level according to the PSS (k = 0.578467). Pre-test cortisol levels correlated with the frequency of using PMR guidelines during winter test periods (k = 0.416138). Stress negatively affects the immune system and poses health risks. Implementing stress reduction techniques in dental/medical education could benefit students and the healthcare system.
... Secretion of cortisol follows a diurnal pattern, with the lowest concentrations noted at bedtime, and the highest in the early morning hours [11]. Among various aspects of the diurnal cycle that has been studied to investigate potential dysfunction in the HPA axis is the cortisol awakening response (CAR), which represents a sharp increase in cortisol levels over the first 30-45 min following morning awakening [12], knowing that CAR is a distinct feature of the diurnal cycle [13]. It has been introduced as a measure of the HPA axis reactivity to awakening stress, possibly reflecting modifications in the HPA axis activity after stressors [14,15]. ...
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Knowing that biomolecules, such as β-amyrin and α-amyrin, have some pharmacological effects, the aim of this study was directed towards exploring the protective effect of Tomato Peel and Seed Extract (TPSE) for its soothing function but also for its capacity to modulate the adrenal axis, which is involved in stress response. Ex vivo tests were carried out on skin explants to evaluate the effectiveness of TPSE formulated at 0.5% on Calcitonin Gene-Related Peptide (CGRP) and IL-10 release, Kappa Opioid Receptor (KOR), and Caspase 14 expression. An in vivo study combined a clinical evaluation of skin homogeneity and psychological parameters as well as an analysis of salivary cortisol and dehydroepiandrosterone concentrations. All measurements were carried out at the beginning and after 28 days of applying a TPSE face cream. TPSE regulated not only the release of CGRP, IL-10, and the expression of Caspase 14, reflecting anti-neurogenic and anti-inflammatory properties, but also modulated KORs. Twenty-eight days of TPSE application induced a significant decrease in intensity and extent erythrosis, a lower output of salivary cortisol, and a significant increase in pleasant emotions when compared to placebo. These results provide encouragement to continue exploring the impact of cosmetic ingredients on psychophysiological parameters to improve skin health and well-being.
... Upon awakening from night sleep, cortisol, the major glucocorticoid stress hormone in humans, exhibits a burst typically by 50-160 % within thirty to forty-five minutesthat is known as the cortisol awakening response (CAR) (Clow et al., 2010;Pruessner et al., 1997). Since its first discovery, the CAR, a hallmark of the hypothalamus-pituitary-adrenal (HPA) axis activity as well as a crucial point of reference within the healthy cortisol circadian rhythm, is thought to prepare the body for anticipated challenges of the upcoming day (Adam et al., 2006;Elder et al., 2014;Fries et al., 2009;Law et al., 2013). ...
Preprint
Emotion and cognition involve an intricate crosstalk of neural and endocrine systems that support allostatic processes for maintenance of dynamic equilibrium and rapid adaptation for upcoming challenges. As a hallmark of human endocrine activity, the cortisol awakening response (CAR) is recognized to play a critical role in modulating emotional and executive functions. Yet, the underlying mechanisms of such effects remain elusive. By leveraging pharmacological neuroimaging technique and Hidden Markov Modeling of brain state dynamics, we show that the CAR proactively modulates rapid reconfigurations (state) of large-scale brain networks across multi-task demands. Behaviorally, suppression of CAR proactively and selectively impaired accuracy for emotional discrimination task but not for working memory (WM). In parallel, suppressed CAR led to a decrease in the occurrence rate of brain state dominant to emotional processing, but an increase in brain state linking to executive control under high WM demand. Further energy-based analyses revealed an increase in transition frequency and sequence complexity along with an increased entropy during emotional tasks when suppressed CAR, suggesting a decreased energy supply. Moreover, an increased transition frequency was observed when shifting from neutral to emotional conditions, but an opposite pattern during WM task, with n decreased transition frequency shifts from low to high-executive demands. Our findings establish a causal link between CAR and dynamic allocation of neural resources for emotional and executive functions, suggesting a cognitive neuroendocrine account for CAR-mediated proactive effects and human allostasis.
... For all analyses, covariates included the duration of symptoms (in months), age (in years), sex (dichotomous), smoking (dichotomous), wake-up time, depression (Beck's Depression Inventory [BDI] score), state anxiety (State-Trait-Anxiety Inventory [STAI-S] score), total childhood trauma questionnaire (CTQ) score, and menopause (dichotomous) [29]. ...
... Cortisol secretion is affected by the circadian rhythm, with the lowest fluctuations expected in the late afternoon and the highest concentrations of cortisol expected in the morning between 7 and 10 a.m. (The specific time a person wakes has no major influence on the morning cortisol response, and within 30 minutes after waking, the free cortisol level rises from 50% to 75%.) [15]. Salivary cortisol values are affected by a number of factors, including during the body's response to stress: age and gender, endogenous and exogenous sex hormone values (e.g., menstrual cycle, oral contraceptive use, hormone replacement therapy, pregnancy, breastfeeding), certain medications (psychopharmaceuticals, corticosteroids), smoking, energy-rich diets, coffee and alcohol consumption, and exercise [16]. ...
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Academic stress affects students' psychological and physiological well-being. Dental undergraduate programs are known for their demanding curriculum, leading to significant stress symptoms. Objective was to determine if salivary cortisol levels were higher in students exposed to academic stress, assess the relationship between stress severity/temperament and cortisol values, and explore relaxation technique effects. Salivary cortisol was measured at two time points for all participants: before exams and during a relaxation period after summer break. A third measurement was conducted for students with high pre-test cortisol levels who received instructions on progressive muscle relaxation(PMR) before subsequent exams. Additionally, participants completed two questionnaires: Perceived Stress Scale(PSS) and Fisher's Temperament Questionnaire. The group analysis based on the PSS indicated that 39 participants reported high stress. Women demonstrated significantly higher stress than men(p=0.042054). A significant difference in stress levels was observed between Director and Builder temperament types(p=0.029276). Cortisol levels showed a significant decrease from the first measurement to the second measurement, and the third measurement after implementing PMR. The grade in the "Dermatovenereology" course correlated with stress level according to the PSS(k=0.578467). Pre-test cortisol levels correlated with the frequency of using PMR guidelines during winter test periods(k=0.416138). Stress negatively affects the immune system and poses health risks. Implementing stress reduction techniques in dental/medical education could benefit students and the healthcare system.
... Cortisol levels follow a diurnal rhythm characterized by a cortisol peak between 30 and 45 min after awakening, followed by a sharp decline over the next hour or two, and a more gradual decline during the remainder of the day (Fries et al., 2009;Kirschbaum and Hellhammer, 1989;Pruessner et al., 1997). Circulating levels of cortisol can easily be determined from saliva, but also from blood and urine (Spencer and Deak, 2017). ...
Article
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Researchers commonly assess the functioning of the hypothalamic-pituitary-adrenal (HPA) axis by measuring natural fluctuations of its end product cortisol throughout the day or in response to a standardized stressor. Although it is conceivable that an individual releasing relatively more cortisol when confronted with a laboratory stressor does the same in everyday life, inconsistencies remain in the literature regarding associations between diurnal cortisol parameters and cortisol stress responses. Hence, the current meta-analysis aggregated findings of 12 studies to examine overall associations of diurnal cortisol parameters (including total output, diurnal slope, and cortisol awakening response [CAR]) with cortisol stress reactivity and recovery in the Trier Social Stress Test (TSST). There were no significant overall associations of total output, slope, or CAR with stress reactivity. Lower total diurnal cortisol output was significantly related to better stress recovery, whereas diurnal slope and CAR were unrelated to stress recovery. Moderation analyses revealed that associations between diurnal cortisol and cortisol stress responses were dependent on the computation method of cortisol parameters, questioning the convergence and validity of commonly employed measures of stress reactivity and recovery. Overall, it seems that we cannot predict characteristics of the diurnal cortisol rhythm from a one-time measure of stress reactivity in a standardized psychosocial laboratory paradigm.
Article
Context Many studies have moved toward saliva and peripheral blood sampling for studying cortisol, even in relation to disorders of the brain. However, the degree to which peripheral cortisol reflects central cortisol levels has yet to be comprehensively described. Data describing the effect that biological characteristics such as age and sex have on cortisol levels across compartments is also limited. Objective To assess the relationships of cortisol levels across cerebrospinal fluid (CSF), saliva, and plasma (total and free) compartments and describe the effects of age and sex on these relationships. Design Multisite cross-sectional observation study. Setting Samples collected in academic outpatient settings in 2001-2004. Patients or Other Participants Healthy community volunteers (n = 157) of both sexes, aged 20-85 years. Interventions None. Main Outcome Measures This study was a secondary analysis of data collected from a previously published study. Results CSF cortisol correlated more strongly with plasma (r = 0.49, P < .0001) than with saliva cortisol levels. Sex but not age was a significant modifier of these relationships. CSF cortisol levels trended higher with older age in men (R2 = 0.31, P < .001) but not women. Age-related cortisol binding globulin trends differed by sex but did not correlate with sex differences in cortisol levels in any compartment. Conclusion Variability in the correlations between central and peripheral cortisol discourages the use of peripheral cortisol as a direct surrogate for central cortisol measures. Further investigation of how mechanistic drivers interact with biological factors such as sex will be necessary to fully understand the dynamics of cortisol regulation across fluid compartments.
Article
Emotion and cognition involve an intricate crosstalk of neural and endocrine systems that support dynamic reallocation of neural resources and optimal adaptation for upcoming challenges, an active process analogous to allostasis. As a hallmark of human endocrine activity, the cortisol awakening response (CAR) is recognized to play a critical role in proactively modulating emotional and executive functions. Yet, the underlying mechanisms of such proactive effects remain elusive. By leveraging pharmacological neuroimaging and hidden Markov modeling of brain state dynamics, we show that the CAR proactively modulates rapid spatiotemporal reconfigurations (state) of large-scale brain networks involved in emotional and executive functions. Behaviorally, suppression of CAR proactively impaired performance of emotional discrimination but not working memory (WM), while individuals with higher CAR exhibited better performance for both emotional and WM tasks. Neuronally, suppression of CAR led to a decrease in fractional occupancy and mean lifetime of task-related brain states dominant to emotional and WM processing. Further information-theoretic analyses on sequence complexity of state transitions revealed that a suppressed or lower CAR led to higher transition complexity among states primarily anchored in visual-sensory and salience networks during emotional task. Conversely, an opposite pattern of transition complexity was observed among states anchored in executive control and visuospatial networks during WM, indicating that CAR distinctly modulates neural resources allocated to emotional and WM processing. Our findings establish a causal link of CAR with brain network dynamics across emotional and executive functions, suggesting a neuroendocrine account for CAR proactive effects on human emotion and cognition.
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Background: The cortisol awakening response (CAR) is a pivotal component of the body’s stress response, yet its dynamics under repeated acute stress and its interplay with immune biomarkers remain inadequately understood. Methods: This study examined 80 second-year military medical students undergoing a 5-day intensive surgical simulation designed to elicit stress responses. Salivary samples were collected daily upon waking and 30 min thereafter to measure cortisol and a panel of cytokines using bead-based multiplex ELISA. Results: Analysis revealed a significant blunting of the CAR on the third day of training (p = 0.00006), followed by a recovery on the fourth day (p = 0.0005). Concurrently, specific cytokines such as CXCL1 (r = 0.2, p = 0.0005), IL-6 (r = 0.13, p = 0.02), IL-10 (r = 0.14, p = 0.02), and VEGF-A (r = 0.17, p = 0.003) displayed patterns correlating with the CAR, with increased strength of associations observed when assessing cytokine levels against the CAR of the preceding day (CXCL1 r = 0.41, p = 0.0002. IL-6 r = 0.38, p = 0.0006. IL-10 r = 0.3, p = 0.008. VEGF-A r = 0.41, p = 0.0002). Conclusions: These results suggest a temporal relationship between stress-induced cortisol dynamics and immune regulation. The CAR pattern demonstrated in this study may represent induction of and recovery from psychological burnout. Moreover, the observed cytokine associations provide insight into the mechanisms by which stress can influence immune function. The results may have broader implications for managing stress in high-performance environments, such as military and medical professions, and for identifying individuals at risk of stress-related immune suppression.
Article
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.
Article
Aims Peripheral cortisol represents one biological measure of the hypothalamic–pituitary–adrenal (HPA) axis, a significant component of the stress system, which is altered by chronic alcohol consumption. However, whether heavy alcohol use affects the HPA axis differentially between the sexes and whether basal cortisol levels are a biomarker of prospective alcohol intake is unknown. Methods We recruited light moderate (LM) and binge-heavy (BH) drinkers of alcohol (n = 118). Repeated fasting morning cortisol levels were studied over a 2-hour period to assess basal levels while participants underwent a neuroimaging scan. Results Significantly higher average cortisol levels in BH compared to LM groups across four timepoints were observed (P < .018). Overall sex differences were observed with women showing higher initial cortisol levels at the first timepoint with a blunted decrease over the morning relative to men (P < .003). Average morning cortisol differentially predicted prospective future 30-day daily reports of alcohol consumption by sex and group, such that LM males had a positive significant relationship and BH males had a negative non-significant relationship between cortisol and drinking. Conclusions Findings indicate that morning plasma cortisol is upregulated in the BH vs. LM group. Although females had higher initial morning cortisol levels, BH males showed a dysregulated negative relationship between stress and binge drinking in contrast to the LM group. Future work should further investigate the role of cortisol and other stress hormones as biomarkers of problematic drinking behaviors in men and women.
Article
Several autism‐related characteristics, such as social difficulties, may contribute to high perceived stress and increased exposure to stressful life events in some autistic individuals. Repeated exposure to stress might lead to the dysfunction of the hypothalamic–pituitary‐adrenocortical‐axis and be a vulnerability factor for developing mental health difficulties. Previous studies show contradictory findings on salivary cortisol in autism. In the current study, we investigated diurnal cortisol profiles in autistic adolescents and young adults, as well as their associations with social difficulties, stress exposure, and mental health symptoms. Autistic ( n = 48, M age = 17.6) and nonautistic ( n = 51, M age = 18.4) participants collected salivary cortisol at home six times a day for 2 days. Social difficulties, exposure to stressful life events/bullying, and mental health symptoms were assessed with questionnaires and clinical interviews. Similar diurnal cortisol slopes (DCS) and cortisol awakening responses were observed between the groups, but autistic participants showed higher total cortisol output (AUC G , area under the curve with respect to ground) during the day ( b = 19.09, p = 0.009). In the autistic group, more severe social difficulties were associated with flatter DCS ( b = 0.01, p = 0.007). Finally, cortisol alterations were associated with self‐reported mental health symptoms, especially in autistic females in analyses uncorrected for multiple comparisons. In conclusion, our results do not indicate autism‐related group‐level alterations in most diurnal cortisol measures, but autistic youth showed higher total cortisol (AUC G ) compared with nonautistic peers. More detailed investigation of interindividual variability in cortisol profiles within autistic people might give us important insights into vulnerability to developing stress‐related mental health difficulties.
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We perceive color everywhere and on everything that we encounter in daily life. Color science has progressed to the point where a great deal is known about the mechanics, evolution, and development of color vision, but less is known about the relation between color vision and psychology. However, color psychology is now a burgeoning, exciting area and this Handbook provides comprehensive coverage of emerging theory and research. Top scholars in the field provide rigorous overviews of work on color categorization, color symbolism and association, color preference, reciprocal relations between color perception and psychological functioning, and variations and deficiencies in color perception. The Handbook of Color Psychology seeks to facilitate cross-fertilization among researchers, both within and across disciplines and areas of research, and is an essential resource for anyone interested in color psychology in both theoretical and applied areas of study.
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Objectives The hypothalamic–pituitary–adrenal (HPA) axis and its primary end product, the glucocorticoid cortisol, are major components of the evolved human stress response. However, most studies have examined these systems among populations in high‐income settings, which differ from the high pathogen and limited resource contexts in which the HPA axis functioned for most of human evolution. Methods We investigated variability in diurnal salivary cortisol patterns among 298 Indigenous Shuar from Amazonian Ecuador (147 males, 151 females; age 2–86 years), focusing on the effects of age, biological sex, and body mass index (BMI) in shaping differences in diurnal cortisol production. Saliva samples were collected three times daily (waking, 30 minutes post‐waking, evening) for three consecutive days to measure key cortisol parameters: levels at waking, the cortisol awakening response, the diurnal slope, and total daily output. Results Age was positively associated with waking levels and total daily output, with Shuar juveniles and adolescents displaying significantly lower levels than adults ( p < .05). Sex was not a significant predictor of cortisol levels ( p > .05), as Shuar males and females displayed similar patterns of diurnal cortisol production across the life course. Moreover, age, sex, and BMI significantly interacted to moderate the rate of diurnal cortisol decline ( p = .027). Overall, Shuar demonstrated relatively lower cortisol concentrations than high‐income populations. Conclusions This study expands the documented range of global variation in HPA axis activity and diurnal cortisol production and provides important insights into the plasticity of human stress physiology across diverse developmental and socioecological settings.
Article
Recently, the cortisol awakening response (CAR) has been focused as an index of chronic stress. Chronic, accumulated stress through burnout is known to result in uncontrollable HPA axis stress responses that cause abnormal CAR. However, the effects of burnout tendency on CAR in athletes remain unclear. This study examined the effect of burnout tendency on CAR in athletes. Participants were top-level female university athletes (N=45). Among them, the results of 40 participants were analyzed after excluding five participants that experienced measurement problems. The burnout tendency was evaluated using the Athletic Burnout Inventory (ABI). The participants were classified into the High BO group (N=12) with high burnout scores and the Low BO group (N=28) with low burnout scores. They were instructed to collect saliva at home, just after waking up, as well as 15 minutes, and 30 minutes later. The concentration of cortisol in saliva was estimated using the Enzyme-Linked Immuno-Sorbent Assay (ELISA). The results revealed higher CAR and AUCG tendencies in the High BO group compared to the Low BO group. However, this possibility has not been sufficiently supported statistically in the current study. We should revalidate these findings by ensuring an adequate number of samples estimated from the effect size. These findings indicate a new physiological index for assessing burnout tendency, which could contribute to better understanding the physiological mechanisms of burnout onset.
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Hormone and substrate responses to mild and heavy treadmill exercise were compared in women who used oral contraceptives (OC group; n = 7) and in normally menstruating women (control group; n = 8). Venous blood samples were obtained before exercise (-5 min), during exercise (15, 30, 45, and 60 min), and 30 min after exercise. All samples were analyzed for glucose, lactate, free fatty acids (FFA), glycerol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), human growth hormone (hGH), cortisol, insulin, estradiol (E2), and progesterone (P). Substrate patterns during exercise were not altered by the phase of the menstrual cycle or OC usage. However, in the OC group the FFA concentrations were consistently higher during mild exercise and the glucose concentrations were lower at rest and during exercise than in the control group (P less than 0.05). No differences in lactate or glycerol responses were observed between the groups (P greater than 0.05). The responses of insulin and hGH to exercise were not related to the OC use per se but rather to the steroid status, either endogenous or exogenous. Specifically, during the steroid phases (OC use phase and luteal phase) 1) insulin concentrations were not quite as markedly reduced (i.e., 12% higher when luteal phase and OC usage phase data were combined; P less than 0.05), and 2) hGH concentrations at rest and during light exercise were higher in the OC group during the OC use phase (P less than 0.05). LH patterns were not affected by exercise (P greater than 0.05), but a slight decrease was found in FSH (P less than 0.05). Increments in P and E2 were observed in the control group in both the follicular and luteal phase (P less than 0.05), but much greater increments in P occurred in the luteal phase than in the follicular phase (P less than 0.05). In contrast to the control group, no increments in P, E2, or cortisol occurred in the OC users during exercise (P greater than 0.05). Therefore the new observations in this study are that 1) insulin and growth hormone respond in a complex manner during exercise with either the phase of the menstrual cycle or the phases of OC use and disuse and 2) the steroid concentrations (P, E2, cortisol) are increased in the controls but not in the OC users during exercise. The latter point suggests that normal steroid increments are due to an increased rate of secretion rather than a decrease in the hepatic clearance of these steroids.(ABSTRACT TRUNCATED AT 400 WORDS)
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The measurement of cortisol in saliva provides the basic scientist as well as the clinician with a reliable tool for investigations of hypothalamus-pituitary-adrenal axis activity. Since saliva samples can be obtained stress-free and independent from medically trained personnel this method may be well suited for use in psychobiological studies. This overview intends to give a comprehensive introduction to the method of salivary cortisol assessment and to briefly discuss its application in different scientific disciplines.
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Evidence from animal studies and clinical observations suggest that the activity of the pituitary-adrenal axis is under significant influence of sex steroids. The present study investigated how a short term elevation of estradiol levels affects ACTH, cortisol, norepinephrine, and heart rate responses to mental stress in healthy men. In a double blind study, 16 men received a patch delivering 0.1 mg estradiol/day transdermally, and age- and body mass index-matched control subjects received a placebo patch. Twenty-four to 48 h later, they were exposed to a brief psychosocial stressor (free speech and mental arithmetic in front of an audience). In response to the psychosocial stressor, ACTH, cortisol, norepinephrine, and heart rate were increased in both experimental groups (all P < 0.0001). However, the estradiol-treated subjects showed exaggerated peak ACTH (P < 0.001) and cortisol (P < 0.002) responses compared to the placebo group. Also, the norepinephrine area under the response curve was greater in the estradiol group (P < 0.05). Although heart rate responses differences failed to reach statistical significance, they, too, tended to be larger in the estradiol group. Neither mood ratings before or after the stressor, nor ratings of the perception of the stressor could explain the observed endocrine response differences. In conclusion, short term estradiol administration resulted in hyperresponses of the pituitary-adrenal axis and norepinephrine to psychosocial stress in healthy young men independent of psychological effects, as assessed in this study.
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To assess the diagnostic potential of salivary cortisol measurements in an outpatient setting we analysed the stability of salivary cortisol and measured salivary cortisol in normals and patients with adrenocortical diseases. In samples of saliva, cortisol was stable over 5 days at 4°C as well as at room temperature. Patients with elevated total serum cortisol due to oestrogen administration showed normal suppression of salivary cortisol after dexamethasone, while serum cortisol was not suppressed in 3 out of 9 cases. Baseline salivary cortisol was decreased in adrenal insufficiency (0.15 ± 0.02 μg/dl) but rose rapidly to increased levels after 25 mg cortisone acetate and remained elevated for 4 hours. Salivary cortisol profiles (7.00-23.00 h) in normals demonstrated the episodic secretion and the typical daily rhythm with very low concentration in the late evening (0.13 ± 0.08 μg/dl). This pattern was significantly altered in patients with Cushing's syndrome, allowing complete separation from normal subjects by sampling from 19.00-23.00 h (p < 0.0001). Moreover, analysis of the coefficient of variation and the episodic spikes of the profiles helped to identify the cause of Cushing's syndrome. We conclude that salivary cortisol measurements are clearly superior to serum cortisol determination in the ambulatory diagnosis of adrenocortical dysfunction.
Article
Free cortisol, heart rate and affective responses to bicycle ergometry were studied in 31 women using oral contraceptives (OC) and 22 control women. While OC users and control women showed significant increases in both free cortisol and heart rate, OC users had significantly attenuated cortisol responses. Individual workload, peak heart rates and affective responses were similar in both groups. No effect of menstrual or pill cycle phase could be observed on the parameters studied. It is concluded that OC users are able to mount a significant free cortisol response to strenuous exercise but the response magnitude is lower than in women who do not use oestrogen-containing medication. Possible mechanisms and health implications are discussed briefly. KEY woms-saliva; ergometry; human; physical stress; cortisol; menstrual cycle phase Strenuous physical exercise is a potent stressor which elicits a wide range of metabolic, endocrine, immune and psychological responses in many species. Among the most prominent changes are decreases in blood glucose levels, increases in oxygen consumption and sympathetic output and elevation of numerous hormones. One of the most frequently studied endocrine effects of physical exercise is the acute secretion of cortisol preceded by a release of adrenocorticotropin (ACTH), vaso-pressin and corticotropin-releasing hormone (CRH). Results from recent studies suggest that the increased level of cortisol following exercise may reflect the body's attempt to counterregulate the metabolic changes in order to avoid damage. For example, if subjects perform physical exercise greater than 60 per cent V02max, cortisol rises in response to fluid loss and decreased electrolyte and carbohydrate level^.'^ Substitution of these
Article
We describe a direct radioimmunoassay for cortisol in 10-microliter volumes of parotid saliva or whole saliva. Binding proteins are absent from these fluids, as demonstrated by the excellent correlation between results for samples assayed directly and by a comparison procedure involving extraction with 1,2-dichloroethane. The direct assay is specific, precise, and had a lower limit of sensitivity of 4 pg per assay tube. Comparison of cortisol concentrations in plasma, parotid saliva, and whole saliva in persons undergoing investigations for assessing adrenal function, including stimulation with cosyntropin (Synacthen) and suppression with dexamethasone, indicated that changes in plasma cortisol concentration were accurately and immediately reflected in saliva from either the parotidgland or whole saliva. A marked circadian rhythm has also been demonstrated for cortisol in parotid-gland saliva and whole saliva. We had to modify the 1,2-dichloroethane extraction procedure for accurate determination of cortisol in parotid saliva and whole saliva of patients undergoing treatment with metyrapone.
Article
It is still discussed controversially to what extent the nocturnal activity of the hypothalamus-pituitary-adrenocortical system depends on sleep and awakening in the morning. Therefore, we investigated the association of plasma ACTH and cortisol levels with undisturbed nocturnal sleep and spontaneous awakening in 14 healthy male subjects (between 2300 h and 1100 h). Between sleep onset and 476.9 min after sleep onset mean plasma cortisol level was significantly (P < 0.01) higher (210 +/- 15 vs. 155 +/- 9 nmol/L) in the group with a shorter (476.9 +/- 15.0 min; n = 7; mean +/- SEM) than in the group with a longer total sleep time (596.9 +/- 14.4 min; n = 7). Spontaneous awakening in the morning was not linked to the presence of any specific sleep stage or to rising plasma ACTH and cortisol levels. However, spontaneous awakening was followed by a brief rise in plasma ACTH and cortisol in both groups. Thereafter, during wakefulness plasma ACTH and cortisol abruptly declined in all subjects irrespective of the time of awakening. The slope of the plasma ACTH and cortisol curves differed significantly (ACTH: P < 0.001; cortisol: P < 0.002, for all subjects) comparing the time after awakening (until 1100 h) with a time interval of identical length before awakening. We conclude that the duration of sleep and nocturnal ACTH and cortisol secretion are interrelated. Furthermore, the data suggest that the endogenous early morning activation of the hypothalamus-pituitary-adrenocortical system is terminated by mechanisms closely associated with awakening.
Article
In four independent studies, sex differences in cortisol responses to psychological stress were investigated in healthy adolescents and adults (total n = 153). Public speaking and mental arithmetic in front of an audience (Studies 1-3) reliably induced increases in free cortisol levels in both sexes with 2- to 4-fold increases above baseline levels. Mean cortisol responses were 1.5- to 2-fold higher in men compared with women. In Study 3, cortisol profiles were additionally investigated after human corticotropin-releasing hormone (h-CRH) and bicycle ergometry until exhaustion. Here, both sexes showed very similar adrenocortical responses. Furthermore, men showed elevated cortisol levels in anticipation of the psychological stress situation without actually having to perform the tasks (Study 4). Under this condition cortisol concentration was unchanged or decreased in women. From these data we conclude that the observed sex difference does not reflect an overall lower responsiveness of the female adrenal cortex. Although these studies do not provide conclusive data, we suggest sex differences in cognitive and/or emotional responses to distressing psychosocial situations which in turn may influence cortisol secretion.
Article
Cortisol 3-(o-carboxymethyl)oxime (C3-CMO) and a commercially available biotin-hydrazide derivative were used to synthesize a C3-CMO-biotin conjugate. C3-CMO was converted into a N-hydroxysuccinimide ester derivative which in a second reaction step was allowed to interact with the hydrazide derivative of biotin. This simple-to-perform synthesis yielded a conjugate suitable for use as a tracer in immunoassays for cortisol measurement. Employing biotin as the primary probe in a competitive solid phase immunoassay allows for variable end point determination by means of commercially available labeled avidin or streptavidin derivatives. Streptavidin-Europium was used in conjunction with the DELFIA-system for time-resolved fluorometric end point measurement (TR-FIA) throughout the study. In addition, colorimetric end point determination (ELISA) using streptavidin-alkaline phosphatase as a secondary probe was established and evaluated. Both forms of this non-isotopic assay showed excellent correlation with a commercially available radioimmunoassay adapted for salivary cortisol measurement. The lower detection limit was 0.43 nM for a 50 microliters salivary sample. The intra-assay coefficient of variation was 6.7, 4.7 and 4.0% at cortisol concentrations of 2.2, 5.5 and 13.2 nM, respectively (n = 37), and the corresponding inter-assay coefficients of variation were 9.0, 8.6 and 7.1% (n = 50). The competitive immunoassay requires 1.5 h incubation time and shows robust and reproducible performance. The C3-CMO-biotin conjugate allows for sensitive and flexible end point determination of salivary cortisol levels in immunoassays.
Article
Recent studies have provided evidence that nocturnal cortisol secretion is coupled to ultradian rhythms of sleep. The present study was designed to specify how exogenous and sleep-related endogenous factors influence nocturnal adrenocorticotropin (ACTH) and cortisol secretion. We compared the influences of (1) temporary sleep deprivation, (2) arousals continuously induced during sleep and, (3) undisturbed sleep (baseline) on pituitary-adrenocortical activity in 10 healthy men. Sleep deprivation (DS) and continuous arousals during sleep (AS) were introduced at the beginning of the second rapid eye movement (REM) sleep period which is an epoch close to the first significant nocturnal rise in plasma cortisol. Compared with the baseline nights, plasma cortisol significantly increased immediately after continuous arousals were started or the subject was awakened and remained awake. Despite this exogenously provoked first cortisol peak, average cortisol release during DS and AS was no higher than during undisturbed sleep. The arousal-induced cortisol burst was followed by a temporary inhibition of cortisol secretion, suggesting that once the subject is aroused (i.e., in stage 1 sleep or awake), the hypothalamus-pituitary-adrenal (HPA) system becomes highly sensitive to negative feedback inhibition. Spontaneously occurring endogenous cortisol peaks of comparable size during undisturbed sleep did not exhibit such a temporary inhibition of cortisol secretion. We hypothesize that sleep attenuates negative feedback inhibition within the HPA system, whereas wakefulness (or stage 1 sleep) reflects increased feedback sensitivity of this system.
Article
To evaluate the hypothesis that endocrine profiles change with aging independently of specific disease states, we examined the age trends of 17 major sex hormones, metabolites, and related serum proteins in 2 large groups of adult males drawn from the Massachusetts Male Aging Study, a population-based cross-sectional survey of men aged 39-70 yr conducted in 1986-89. Group 1 consisted of 415 men who were free of obesity, alcoholism, all prescription medication, prostate problems, and chronic illness (cancer, coronary heart disease, hypertension, diabetes, and ulcer). Group 2 consisted of 1294 men who reported 1 or more of the above conditions. Each age trend was satisfactorily described by a constant percent change per yr between ages 39-70 yr. Free testosterone declined by 1.2%/yr, and albumin-bound testosterone by 1.0%/yr. Sex hormone-binding globulin (SHBG), the major serum carrier of testosterone, increased by 1.2%/yr, with the net effect that total serum testosterone declined more slowly (0.4%/yr) than the free or albumin-bound pools alone. Among the major androgens and metabolites, androstane-3 alpha,17 beta-diol (androstanediol; 0.8%/yr) and androstanediol glucuronide (0.6%/yr) declined less rapidly than free testosterone, while 5 alpha-dihydrotestosterone remained essentially constant between ages 39-70 yr. Androstenedione declined at 1.3%/yr, a rate comparable to that of free testosterone, while the adrenal androgen dehydroepiandrosterone (3.1%/yr) and its sulfate (2.2%/yr) declined 2-3 times more rapidly. The levels of testosterone, SHBG, and several androgen metabolites followed a parallel course in groups 1 and 2, remaining consistently 10-15% lower in group 2 across the age range of the study. Subgroup analyses suggested that obese subjects might be responsible for much of the group difference in androgen level. Serum concentrations of estrogens and cortisol did not change significantly with age or differ between groups. Of the pituitary gonadotropins, FSH increased at 1.9%/yr, LH increased at 1.3%/yr, and PRL declined at 0.4%/yr, with no significant difference between groups 1 and 2.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
In two studies we applied a new stochastic model for the measurement of latent states and traits to salivary cortisol in healthy subjects. Data were analyzed by Linear Structural Relations (LISREL). In the first study, 48 students collected saliva samples on two occasions at 1300h with an interval of six weeks between occasions. Salivary cortisol levels were found to be mainly influenced by situational and/or interactional effects, which determined approximately 75% of the total variance of the hormone data, while only approximately 21% were determined by the latent trait. Measurement unreliability was found to be approximately 4%. In the second study, 54 young mothers collected saliva at 0800h, 1500h, and 2000h for three consecutive days, starting on the second day after delivery of a healthy baby. Early morning salivary cortisol showed high consistency across the three days. Approximately 60% of the total variance in the early morning cortisol samples was determined by the latent trait. For the 1500h and 2000h samples, however, the corresponding proportions of variances amounted only to 33% and 28%, respectively. These results appear to reflect the absence of a clear-cut circadian rhythm in some of the women on the second day after delivery.
Article
The salivary cortisol concentration is an excellent indicator of the plasma free cortisol concentration. To establish its normal and pathological ranges, salivary cortisol concentrations were measured in 101 normal adults, 18 patients with Cushing's syndrome, and 21 patients with adrenal insufficiency. The normal subjects had a mean (+/- SEM) salivary cortisol concentration of 15.5 +/- 0.8 nmol/L (range, 10.2-27.3) at 0800 h and 3.9 +/- 0.2 nmol/L (range, 2.2-4.1) at 2000 h (n = 20). The mean value 60 min after ACTH administration in 58 normal subjects was 52.2 +/- 2.2 nmol/L (range, 23.5-99.4), and it was 1.4 +/- 1.1 nmol/L (range, 1.6-3) at 0800 h in 23 normal subjects given 1 mg dexamethasone 8 h earlier. In patients with primary or secondary adrenal insufficiency (n = 21) the mean salivary cortisol level was 7.5 +/- 0.4 nmol/L (range, 1.9-21.8) 60 min after ACTH. In patients with Cushing's syndrome (n = 7), the mean value after the 1-mg dexamethasone suppression test was 16.1 +/- 7.8 nmol/L (range, 5.8-66.8). No overlap was found between the values in the normal subjects and those in the patients during the dynamic tests. Discrepancies between salivary and total plasma cortisol were found in 8 patients with adrenal insufficiency, which may be explained by the effects of drugs such as thyroid hormones, Op'-dichlorodiphenyldichloroethane, and psychotropic agents. We conclude that salivary cortisol measurements are an excellent index of plasma free cortisol concentrations. They circumvent the physiological, pathological, and pharmacological changes due to corticosteroid-binding globulin alterations and offer a practical approach to assess pituitary-adrenal function.
Article
We have shown evidence challenging the currently prevailing view that 24-h rhythms of a pituitary hormone is released either sleep-related or dependent on a master circadian clock. Instead, the temporal organization of pituitary hormone release appears to be controlled by multiple factors. For every pituitary hormone, intrinsic circadian rhythmicity and sleep-related components interact to produce the overt 24-h pattern of plasma concentrations. Meals and other external factors may also elicit transient changes in the circulating levels of these hormones. Previous studies of alterations of the human circadian organization associated with time shifts or temporal isolation followed the evolution of a single time point throughout the investigation span. Examples of such chronobiological markers are the daily maximum of the rhythm of body temperature and the acrophase of the 24-h profile of plasma cortisol levels. Such markers have been considered to reflect the synchronization of the entire rhythm. The present review indicates that a valid estimation of the adaptation of 24-h hormonal variation to changes in environmental time requires the analysis of more than a single reference point in the waveform and emphasizes the importance of methods providing detailed quantitative descriptions of such waveforms.
Article
Assay of hormones in saliva would be more convenient than assay in blood, but there is no information on the route by which hormones enter saliva, information that would provide insight into the clinical value of such assays. We have examined the mode of entry of various hormones into saliva. The results suggest that unconjugated steroids enter saliva by diffusing through the cells of the salivary glands and that their concentration in saliva does not depend on the rate of saliva production. Conjugated steroids enter saliva via "ultrafiltration" through the tight junctions between the acinar cells, and their concentration in saliva is highly flow-rate dependent. Thyroxin and choriogonadotropin enter saliva via the ultrafiltration route or by contamination of the saliva by plasma or gingival fluid. We conclude that the salivary concentration of unconjugated steroids may usefully reflect the concentration of free (nonprotein-bound) steroids in plasma. Conversely, the concentration of conjugated steroids, thyroxin, and protein hormones such as choriogonadotropin in saliva probably does not reflect their concentration in plasma in any clinically useful way.
Article
Total plasma cortisol measurements may be misleading when there are variations in the plasma cortisol-binding protein capacity resulting from drugs, pregnancy or congenital alterations in cortisol-binding globulin (CBG). Salivary cortisol levels, which represent the free component of plasma cortisol, are less affected by alterations in protein binding and have been used in the investigation of hypothalamic-pituitary-adrenal disorders. This study compares these two indices of adrenal function in conditions of true hypercortisolism and spurious hypercortisolism (resulting from oral contraceptive medication or pregnancy). The circadian variation of cortisol in plasma and saliva was studied in six patients with unequivocal hypercortisolism and compared with normal volunteers. In the normal group, plasma and salivary cortisol levels taken at 0900 h were significantly higher than those taken at 2400 h. Patients with Cushing's syndrome failed to show a significant difference between plasma and salivary cortisol levels collected at 0900 and 2400 h. Five patients with pituitary-dependent Cushing's disease, one patient with an adrenal carcinoma causing Cushing's syndrome and seven normal subjects each received a dexamethasone suppression test using a continuous infusion of dexamethasone sodium phosphate at a rate of 1 mg/h. There was no significant difference in the half-life disappearance rate of endogenous cortisol in either plasma or saliva comparing grouped data from patients with pituitary-dependent Cushing's disease with that of normal subjects. Failure of suppression of both plasma and salivary cortisol levels was observed in the one patient with adrenal carcinoma during dexamethasone infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
In two studies, saliva cortisol responses to the psychological stress of public speaking and mental arithmetic were investigated in women using oral contraceptives (OC; n = 28) and in control women (n = 29). While no significant differences in baseline levels were observed, altered adrenocortical responses were found in OC users. These women showed significantly attenuated cortisol responses to the experimental stressor in both studies, with peak cortisol levels only slightly elevated above baseline levels. These differences could not be attributed to affective responses as indicated in ratings on visual analogue scales assessing subjective stress responses (Study 2). A comparison between control women and men (n = 19) again revealed the previously reported result of larger cortisol responses to psychological stress in males. We conclude that the use of OC may interfere with the adrenocortical response to psychological stress and should therefore be viewed as an important intervening variable. While it appears that differences at a supra-adrenal site is responsible for the observed cortisol hyporesponsiveness in OC users, the physiological mechanisms remain to be elucidated.
Article
In the present study the hypothesis was tested that in normal human aging an insensitivity of the glucocorticoid feedback signals is acquired. Thus, 40 healthy elderly (mean age: 69 +/- 5 years) and 20 younger (mean age: 34 +/- 8 years) individuals underwent a combined dexamethasone suppression/CRH-stimulation test. Cortisol secretion after dexamethasone (DEX) pretreatment and before CRH was increased in the older age group, but none of the subjects escaped DEX-induced suppression of cortisol. However, after additional CRH administration to the DEX-pretreated volunteers, the older group released significantly more cortisol than their young counterparts. Within the group of the elderly only, a positive correlation between BASAL, DEX-pretreated cortisol concentration and post-CRH steroid responses was found. Gender profoundly affected DEX/CRH-test outcome: females, regardless of age, had an increased hormonal secretion in comparison to males. It is concluded that, during human aging, adaptive changes in glucocorticoid receptors take place, allowing for the system to maintain "peripheral" glucocorticoid homeostasis, but that more sophisticated challenge procedures such as the DEX/CRH test reveal an age-related increase in HPA system activity.
Article
Few data are available on the reliability of measurements of adrenocortical and corticotroph hormones for use in clinical pharmacology. Two placebo controlled cross-over trials in 20 normal healthy male subjects offered the opportunity to perform three repeat samplings of adrenocortical and corticotroph hormones at 1 to 5 week intervals during the placebo periods. Measurements of baseline levels of plasma, salivary and urinary cortisol, plasma adrenocorticotroph hormone (ACTH), lipotrophic hormone (LPH), beta-endorphin, post tetracosactrin levels of plasma and salivary cortisol, post corticotrophin releasing hormone (CRH)-lysine vasopressine (LVP) levels of plasma cortisol, ACTH and LPH; and post metyrapone levels of plasma cortisol and 11-deoxycortisol (compound S), ACTH, LPH, beta-endorphin were performed in the same laboratory. The reliability of the measurements was estimated by computing the intraclass correlation coefficient (R) and by using Altman-Bland graphical method. The Rs of baseline parameters varied from 0.18 (for 08.00 h salivary cortisol) to 0.55 (for 08.00 h plasma cortisol and nocturnal urinary cortisol). In contrast, parameters obtained after direct stimulation or inhibition of the producing targets were much more reliable: Rs were above 0.80 for post tetracosactrin levels of plasma and salivary cortisol, post CRH-LVP levels of plasma ACTH and LPH. The Rs were below 0.50 for post metyrapone levels of plasma 11-deoxycortisol, ACTH, LPH and beta-endorphin. The interval between sampling did not affect R estimates. These data show that peak levels of plasma cortisol and ACTH after direct stimulation are highly reliable whereas baseline and main post-metyrapone levels are not.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
To define the chronobiology of glucose tolerance and insulin secretion in obesity, nine obese men and nine lean men were studied during constant glucose infusion for 53 h, including 8 h of nocturnal sleep, 28 h of continuous wakefulness, and 8 h of daytime sleep. Blood samples were collected at 20-min intervals to assay glucose, insulin, C-peptide, cortisol, and GH. Sleep was polygraphically monitored. Abnormal temporal profiles of glucose regulation were observed during wakefulness and sleep in obese subjects. During daytime hours, the normal profile of glucose tolerance was reversed, as an improvement, rather than a deterioration, was observed from morning to late evening. This reversal of the daytime pattern appeared to be caused by a dual defect in glucose regulation during the previous night. Indeed, during early sleep, GH secretion was markedly reduced, and the nocturnal rises of glucose and insulin secretion were dampened. During late sleep, obese subjects failed to suppress insulin secretion and plasma glucose, resulting in high morning levels. Comparisons of metabolic and hormonal patterns during nocturnal and daytime sleep suggest that the failure to suppress insulin secretion in late sleep may reflect a relative insensitivity of the beta-cell to acute inhibitory effects of cortisol in addition to insulin resistance.
Article
In an accompanying paper, we discussed the relevance of biological uniqueness for research in physiology and medicine. We proposed the concepts of subject-specific homeostasis, or 'intrinsic' homeostasis. Here, we illustrate this concept with the example of the endocrine 'fingerprint'. 9 hormones were measured in the blood of 8 normal subjects during 2 consecutive mornings, under a standardised resting condition. The concentrations of the hormones were subject-specific. They varied up to 6-fold between subjects, but were stable from one day to the next for each individual. TSH and FSH showed the wider inter-individual range of values, together with a very high level of day-to-day stability (r = 0.99 in both cases). In contrast, the inter-individual range of cortisol concentration was the smallest (1.5-fold) and the day-to-day stability of cortisol concentrations within each subject was low. A total of 21 non-hormonal variables were also measured. They varied less than hormones between subjects, but, with the exception of the electrolytes, most showed stability over the 2 days of sampling. We conclude that the organisation of hormonal and non-hormonal homeostasis varies between subjects to a greater extent than generally acknowledged and suggest that these differences express subject-specific constraints in the organization of homeostasis.