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The daily rhythm of the hypothalamo-pituitary-adrenal (HPA) axis is regulated by the central clock in the suprachiasmatic nucleus. Cortisol, a glucocorticoid, acts as a secondary messenger between the central clock and the peripheral tissues. Changes in clock time, as seen in shift workers, alters the HPA axis and results in metabolic disturbances associated with ill health. Depression, anorexia nervosa and obstructive sleep apnoea, are associated with cortisol rhythm phase shifts and increased cortisol exposure. Higher nocturnal cortisol exposure is observed in patients with Cushing's syndrome and adrenal incidentalomas with autonomous cortisol secretion and is associated with insulin resistance, and increased cardiovascular risk and mortality. A decrease in cortisol rhythm amplitude is seen in adrenal insufficiency, and despite replacement, patients have an impaired quality of life and increased mortality. Research on cortisol replacement has focused on replacing the cortisol daily rhythm by subcutaneous hydrocortisone infusions and oral modified release hydrocortisone formulations with the aim of improving disease control and quality of life.

Studies with animals of both sexes show that the adrenal glands release progesterone in addition to cortisol in response to stress. However, little is known about the progesterone response to stress in naturally cycling women. We investigated the effect of stress on estradiol, progesterone, and cortisol levels in women during the follicular phase of the menstrual cycle. We found that physical stress (the cold pressor test) had no effect on estradiol levels, but increased progesterone and cortisol. We also found positive correlations between baseline progesterone and cortisol levels, as well as between the change in progesterone and cortisol before and after water exposure in both the stress and control sessions. Mediation analyses revealed during the stress session, the change in progesterone from baseline to 42-min post-stress onset was mediated by the magnitude of change in cortisol levels across the same time span. Overall, these findings reveal that progesterone released in response to stress as observed in animals and men extends to women during the low ovarian output follicular phase of the menstrual cycle, and that the mechanism of release may be similar to the mechanism of cortisol release., Highlights • Progesterone rises in response to stress during the follicular phase. • Baseline progesterone was associated with greater cortisol response to stress. • Cortisol response to stress mediated progesterone responses to stress.

24 hour cortisol and 17OHP profiles allow for fine tuning of cortisol replacement therapy. Profiles answer the following questions. (1) Is the cortisol distribution correct over the 24 hour period? (2) Are there periods where cortisol over stacking is occurring? (3) Are the cortisol peaks too high or too low and occurring at the right times of the day? (4) Is the dose lasting long enough and are there periods where there is no cortisol in the blood stream? (5) What effect is cortisol having on 17OHP? Are the 17OHP levels too high, indicating more cortisol is needed or are the 17OHP levels too low, meaning the dose needs to be adjusted by lowering and/or does the time at which the dose is taken, need altering? (6) Do other factors influence 17OHP, such as pain from cannula insertion , adrenal rests or polycystic ovaries? The time interval between samples is crucial. If the gap is too long then the peak values will be underestimated and the interaction of cortisol and 17OHP will be unclear. An interval of 60 minutes is ideal and 120 minutes is the longest gap possible before the information degrades. Other hormones can be studied to check puberty status. Adrenal androgen levels can also be measured which can be variable over the 24 hour period. This can inform whether testosterone/estrogen levels are being influenced by adrenal androgens.

17-Hydroxyprogesterone (17OHP) is a steroid hormone. In CAH 17OHP is used as a marker of how active the adrenal glands are, as it indicates how much ACTH is produced by the pituitary. Our data demonstrate that 17OHP measurements do not accurately reflect the amount of cortisol present in the blood stream and therefore it cannot be used as a single measurement to assess and fine tune doses. There is a lag between the effect cortisol has on 17OHP known as the feedback loop system so that a trough measure of 17OHP follows 60–120 minutes after a cortisol peak. Sampling has to take this into account. If the doses deliver excessive cortisol peaks this length of time increases, if the doses are consistently high, 17OHP production can be switched off completely. 17OHP is influenced by pain and illness induced stress, painful blood sampling and it also varies during the menstrual cycle. Adrenal rest tissue can also produce 17OHP and this is often regulated through aberrent receptor expression. Cortisol dictates 17OHP level responses; therefore normalisation of 17OHP and androstenedione will follow optimal cortisol replacement. The key is to optimise cortisol replacement. Other markers such as androstenedione have the same problem and testosterone is too insensitive to use as it only rises when the condition is poorly controlled. Single samples pre dose of 17OHP can lead to inappropriate changes in dosing. Cortisol controls 17OHP production by regulating ACTH. 17OHP production responds to ACTH. 17OHP does not control cortisol or instruct the adrenal glands to produce cortisol; therefore the amount of replacement cortisol present in the blood cannot be assessed on measurement of 17OHP alone.

Contains fulltext : 167424.pdf (Publisher’s version ) (Open Access) Hypothalamic-pituitary-adrenal (HPA) axis functioning is characterized by the baseline production of cortisol following a circadian rhythm, as well as by the superimposed production of cortisol in response to a stressor. However, it is relatively unknown whether the basal cortisol circadian rhythm is associated with the cortisol stress response in children. Since alterations in cortisol stress responses have been associated with mental and physical health, this study investigated whether the cortisol circadian rhythm is associated with cortisol stress responses in 6-year-old children. To this end 149 normally developing children (Mage = 6.09 years; 70 girls) participated in an innovative social evaluative stress test that effectively provoked increases in cortisol. To determine the cortisol stress response, 6 cortisol saliva samples were collected and 2 cortisol stress response indices were calculated: total stress cortisol and cortisol stress reactivity. To determine children's cortisol circadian rhythm 8 cortisol circadian samples were collected during 2 days. Total diurnal cortisol and diurnal cortisol decline scores were calculated as indices of the cortisol circadian rhythm. Hierarchical regression analyses indicated that higher total diurnal cortisol, as well as a smaller diurnal cortisol decline, were both uniquely associated with higher total stress cortisol. No associations were found between the cortisol circadian rhythm indices and cortisol stress reactivity. Possible explanations for the patterns found are links with children's self-regulatory capacities and parenting quality. 7 p.

Sleep is divided into four stages and cortisol increases in the blood from low values in the evening during Stage 3 sleep which is entered quite quickly after falling asleep. It is not clear if sleep determines cortisol appearance, as cortisol is more attuned to the light/dark cycle than sleep itself. It has been suggested taking hydrocortisone late in the evening causes problems in trying to fall asleep. Often adults are advised to take the last dose of hydrocortisone at 18:00 (6 p.m.) but this leads to long periods of time without cortisol overnight. Careful sleep studies have shown the time sleep starts, quality and duration of sleep, is not affected by the timing of hydrocortisone dosing. Cortisol levels are increased but the circadian rhythm is maintained in people with depression. Whether the altered amount of cortisol in these situations leads to the depression or is a secondary effect of whatever causes the problem in the first place, is not clear. Although mood changes can be associated with any of the glucocorticoids, both prednisolone and dexamethasone appear to have higher rates of mood changes associated with their use.

Dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis is believed to play a role in the pathophysiology of depression. To investigate mechanisms that may underlie this effect, we examined several indices of HPA axis function – specifically, diurnal cortisol slope, cortisol awakening response, and suppression of cortisol release following dexamethasone administration – in 26 pre-menopausal depressed women and 23 never depressed women who were matched for age and body mass index. Salivary cortisol samples were collected at waking, 30 min after waking, and at bedtime over three consecutive days. On the third day, immediately after the bedtime sample, participants ingested a 0.5 mg dexamethasone tablet; they then collected cortisol samples at waking and 30 min after waking the following morning. As predicted, depressed women exhibited flatter diurnal cortisol rhythms and more impaired suppression of cortisol following dexamethasone administration than non-depressed women over the three sampling days. In addition, flatter diurnal cortisol slopes were associated with reduced cortisol response to dexamethasone treatment, both for all women and for depressed women when considered separately. Finally, greater self-reported depression severity was associated with flatter diurnal cortisol slopes and with less dexamethasone-related cortisol suppression for depressed women. Depression in women thus appears to be characterized by altered HPA axis functioning, as indexed by flatter diurnal cortisol slopes and an associated impaired sensitivity of cortisol to dexamethasone. Given that altered HPA axis functioning has been implicated in several somatic conditions, the present findings may be relevant for understanding the pathophysiology of both depression and depression-related physical disease.

Women who drink alcohol during pregnancy are at high risk of giving birth to children with neurodevelopmental disorders. Previous reports from our laboratory have shown that third trimester equivalent binge alcohol exposure at a dose of 1.75 g/kg/day results in significant fetal cerebellar Purkinje cell loss in fetal sheep and that both maternal and fetal adrenocorticotropin (ACTH) and cortisol levels are elevated in response to alcohol treatment. In this study, we hypothesized that repeated elevations in cortisol from chronic binge alcohol are responsible at least in part for fetal neuronal deficits. Animals were divided into four treatment groups: normal control, pair-fed saline control, alcohol and cortisol. The magnitude of elevation in cortisol in response to alcohol was mimicked in the cortisol group by infusing pregnant ewes with hydrocortisone for 6 h on each day of the experiment, and administering saline during the first hour in lieu of alcohol. The experiment was conducted on three consecutive days followed by four days without treatment beginning on gestational day (GD) 109 until GD 132. Peak maternal blood alcohol concentration in the alcohol group was 239 ± 7 mg/dl. The fetal brains were collected and processed for stereological cell counting on GD 133. The estimated total number of fetal cerebellar Purkinje cells, the reference volume and the Purkinje cell density were not altered in response to glucocorticoid infusion in the absence of alcohol. These results suggest that glucocorticoids independently during the third trimester equivalent may not produce fetal cerebellar Purkinje cell loss. However, the elevations in cortisol along with other changes induced by alcohol could together lead to brain injury seen in the fetal alcohol spectrum disorders.

Stress-induction procedures designed to increase cortisol levels in infants have been ineffective in many studies. One reason might be that infants did not have sufficient time to settle into the laboratory environment prior to the start of the stress induction, and thus already had high baseline levels of cortisol. In this study we investigate whether an extended warm-up period reduces infants’ ( N = 22) cortisol levels. Fifteen-month-old infants’ saliva cortisol was measured upon arrival at the laboratory. Then, they were allowed to play with their parent. After 30 min, cortisol was measured again. There was a decrease in cortisol after 30 min of free play. Our study suggests that infants’ cortisol levels decrease when infants have the opportunity to acclimatize to the test environment. An extended warm-up phase prior to stress induction procedures might be necessary to reliably increase cortisol levels in infants.

Cortisol, the major physiological end product of the hypothalamic-pituitary-adrenal axis, is usually associated with stress and negative affect. However, a new body of research highlights the complex, adaptive significance of elevated cortisol within individuals in everyday life. Whereas most studies do not have the power to test the dynamic transactions between cortisol and affect within a person throughout the entire waking day, we employed an intensive study protocol analyzing hourly diary reports of affect in relation to hourly salivary cortisol samples among 24 healthy adults from morning to bedtime, across 2 consecutive weekdays (N = 862 total samples). Utilizing multileveling modeling and focusing on within-person effects, we examined whether momentary increases in cortisol could be mood protective, or energy enhancing, in everyday life, supporting the cortisol boost hypothesis. Results revealed no significant associations between cortisol and current affective state; however, within-person increases in cortisol were significantly associated with subsequent rises in activeness, alertness, and relaxation, and trend-level reductions in stress and nervousness. This study adds to growing evidence that cortisol plays a positive role in regulating affect in everyday life. (PsycINFO Database Record

The cortisol awakening response (CAR) is the change in cortisol concentration that occurs in the first hour after waking from sleep. It is typically assessed using salivary cortisol samples immediately after waking and then at intervals over the next hour. The CAR has emerged as an important aspect of hypothalamic-pituitary-adrenocortical axis function because it is regulated differently from cortisol output over the rest of the diurnal cycle. It has also been related to stress, affective disorders, and physical health risk. This chapter discusses the origins and measurement of the CAR and its relationship with sleep-waking cycles, acute and chronic stress, depression, and health outcomes.

It is challenging to measure long-term endocrine stress responses in animals. We investigated whether cortisol extracted from dog hair reflected the levels of activity and stress long-term, during weeks and months. Hair samples from in total 59 German shepherds were analysed. Samples for measuring cortisol concentrations were collected at three occasions and we complemented the data with individual scores from the Canine Behavioural Assessment and Research Questionnaire (C-BARQ). Generalised linear mixed model (GLMM) results showed that hair cortisol varied with season and lifestyle: competition dogs had higher levels than companion, and professional working dogs, and levels were higher in January than in May and September. In addition, a positive correlation was found between the cortisol levels and the C-BARQ score for stranger-directed aggression (r = 0.31, P = 0.036). Interestingly, the factor "playing often with the dog" (r = -0.34, P = 0.019) and "reward with a treat/toy when the dog behaves correctly" (r = -0.37, P = 0.010) correlated negatively with cortisol levels, suggesting that positive human interactions reduce stress. In conclusion, hair cortisol is a promising method for revealing the activity of the HPA-axis over a longer period of time, and human interactions influence the cortisol level in dogs. Funding Agencies|Formas; European Research Council (ERC) [322206]; County Council of Ostergtland, Sweden

Aims Hypothalamic-pituitary-adrenal (HPA) axis activity may prove a viable biomarker for identifying those susceptible to alcohol use disorders. The purpose of this study was to examine the relation of the age at which adolescents begin drinking with diurnal and stress cortisol. Design Adolescents' diurnal cortisol levels on a normal day and cortisol levels during a stress procedure were examined in relation to the age of onset of alcohol use. Setting and participants All adolescents (aged 14-20 years) were part of a general population study in the Netherlands (n=2286). Measurements Ten assessments of salivary cortisol taken on a normal day (diurnal cortisol), as well as during a social stress procedure (stress cortisol) were used as indicators of HPA axis activity. Findings The age at which the first alcoholic drink was consumed varied as a function of cortisol levels at the onset of as well as during the stress procedure. Those who began drinking at an earlier age showed lower cortisol levels at the onset of the stressful tasks (r 2=0.14, P

Background: Knowledge of the diurnal cortisol response to acute stress in healthy individuals can help us better understand the physiological and health effects of chronic stress. Objective: To compare the diurnal patterns of cortisol secretion of 15 medical students 2 weeks before a major written examination (control phase) and 2 weeks later at the time of the examination (acute stress phase). Design: Interrupted time series within-subjects. Results: During the acute stress phase, less cortisol was secreted over the course of the day, as demonstrated by a more prolonged and steeper decline in cortisol levels. In addition, higher cortisol levels were present in the evening. Despite these changes in the usual diurnal pattern, overall exposure to cortisol remained the same for both phases. Conclusions: The results of this study suggest that specific adaptations to the diurnal pattern of cortisol are made in the face of acute stress, important information for understanding cortisol regulation in health and illness.

Previous studies have shown that situations relevant for human mating can affect the levels of many hormones. This study focused on the hypothalamus-pituitary-adrenal axis by measuring salivary cortisol levels in 84 young men prior to and after a period of short social contact with a woman or man. Results showed that after contact with another man the cortisol levels of the participants declined according to the circadian release pattern of cortisol. However, cortisol levels in men declined less when they had contact with a woman. Furthermore, cortisol levels of men increased when they perceived the woman with whom they had contact as attractive. Our findings provide indirect evidence for the role of the hypothalamus-pituitary-adrenal axis in human courtship. During social contact with attractive women, moderate increases in cortisol levels may reflect apprehension over an opportunity for courtship. (C) 2010 Elsevier Inc. All rights reserved.

Increased hypothalamic-pituitary-adrenal (HPA) activation, culminating in elevated circulating cortisol levels is a fundamental response to stressors. In animals, this neuroendocrine change is highly reliable and marked (approximately 5-10-fold elevations), whereas in humans, the increase of cortisol release is less pronounced, and even some potent life-threatening events (anticipation of surgery) only elicit modest cortisol increases. Meta-analysis of factors that influenced the increase of cortisol release in a laboratory context pointed to the importance of social evaluative threats and stressor controllability in accounting for the cortisol rise. The present meta-analysis, covering the period from 1978 through March 2007, was undertaken to identify the factors most closely aligned with cortisol increases in natural settings. It appeared that stressor chronicity was fundamental in predicting cortisol changes; however, this variable is often confounded by the stressor type, the stressor's controllability, as well as contextual factors, making it difficult to disentangle their relative contributions to the cortisol response. Moreover, several experiential factors (e.g. previous stressor experiences) may influence the cortisol response to ongoing stressors, but these are not readily deduced through a meta-analysis. Nevertheless, there are ample data suggesting that stressful events, through their actions on cortisol levels and reactivity, may influence psychological and physical pathology.

Although plasma corticosterone is considered the main glucocorticoid involved in regulation of stress responses in rodents, the presence of plasma cortisol and whether its level can be used as an indicator for rodent activation of stress remain to be determined. In this study, effects of estrous cycle stage, circadian rhythm, and acute and chronic (repeated or unpredictable) stressors of various severities on dynamics and correlation of serum cortisol and corticosterone were examined in mice. A strong (r = 0.6–0.85) correlation between serum cortisol and corticosterone was observed throughout the estrous cycle, all day long, and during acute or repeated restraints, chronic unpredictable stress and acute forced swimming or heat stress. Both hormones increased to the highest level on day 1 of repeated-restraint or unpredictable stresses, but after that, whereas the concentration of cortisol did not change, that of corticosterone showed different dynamics. Thus, whereas corticosterone declined dramatically during repeated restraints, it remained at the high level during unpredictable stress. During forced swimming or heat stress, whereas cortisol increased to the highest level within 3 min., corticosterone did not reach maximum until 40 min. of stress. Analysis with HPLC and HPLC-MS further confirmed the presence of cortisol in mouse serum. Taken together, results (i) confirmed the presence of cortisol in mouse serum and (ii) suggested that mouse serum cortisol and corticosterone are closely correlated in dynamics under different physiological or stressful conditions, but, whereas corticosterone was a more adaptation-related biomarker than cortisol during chronic stress, cortisol was a quicker responder than corticosterone during severe acute stress.

In healthy, non-challenged individuals, the secretion of cortisol typically follows a diurnal profile characterized by a peak in the period following waking (cortisol awakening response) and a gradual decline throughout the day. In addition, cortisol secretion is increased in response to acutely stressful stimuli, particularly stressors involving social evaluation. The current study is the first to assess the impact of an anticipated acute laboratory stressor upon the typical diurnal pattern of HPA activation and relationship to acute cortisol secretion. A sample of 23 healthy young adults provided salivary cortisol samples at four time points (immediately upon awakening, 30-min post-awakening, 1200 h and before bed) on 2 consecutive days. On the second day, participants attended the laboratory and undertook an anticipated acute socially evaluative stressor immediately following provision of their 1200 h saliva sample. Heart rate, blood pressure and mood were recorded immediately before and after the stressor and at 10 and 20 min post-stressor along with additional salivary cortisol samples. Typical patterns of cortisol secretion were observed on both days and exposure to the laboratory stressor was associated with the expected increases in cortisol, heart rate, blood pressure and negative mood. However, significant differences in diurnal cortisol secretion were observed between the two days with greater secretion, in particular, during the period following awakening, evident on the day of the anticipated laboratory stressor. Furthermore, secretion of cortisol during the period following awakening was positively related to secretion during the acute reactivity periods. This is the first study to integrate a laboratory stressor into a typical day and assess its impact on indices of diurnal cortisol secretion in an ambulatory setting. The current findings support the notion that the cortisol awakening response is associated with anticipation of the upcoming day and the subsequent demands required of the individual.

BACKGROUND In the quest for biological mechanisms underlying socioeconomic differences in health outcomes, attention has turned to the role of the hypothalamic-pituitary-adrenocortical axis. As there is some evidence that both acute and chronic stress raise cortisol levels, and material hardship is a stressor, we examined the relationship of chronic material hardship with salivary cortisol levels over the day. METHODS The data are from a survey of a sample of poor women aged 18-54. Up to four repeated measures of salivary cortisol levels were obtained from 188 women in this sample and modelled as a diurnal profile. Self-reports of a variety of sources of material hardship over the preceding year were combined into a single scale. Specific dimensions of the subjects' cortisol profiles were compared across levels of material hardship. RESULTS Salivary cortisol varied over the day, and by level of reported material hardship. Upon awakening, salivary cortisol levels were comparable across hardship levels. But soon after waking, women at low levels of hardship experienced both a significantly sharper morning surge and subsequently a sharper decline in salivary cortisol (16.0 and 29.5 nmol/l/h) than women with high hardship levels (5.9 and 24.3 nmol/l/h). These differences in cortisol diurnal pattern tended to be related in a dose-response way to levels of material hardship. CONCLUSIONS Material hardship among poor women is associated with changes in the diurnal rhythms of cortisol, particularly in the waking response, which is blunted in women with high levels of hardship.

Collective evidence indicates that previous exposure to stressful condition might be able to induce changes in brain structure, HPA axis activity and related neurotransmission, and accordingly affect physiological responses to subsequent challenges. During long-term spaceflight, space travelers have to live under the condition of isolation and confinement in the spacecraft for a long period. It is still largely unknown if this kind of chronic stress burden can induce any long-lasting changes. To address this question, following 520-d isolation and confinement simulating a flight to Mars, the participants and a matched control group were exposed to an acute stress challenge called parabolic flight. Brain cortical activity, HPA axis activity, and sympathetic adrenal-medullary system response were monitored by EEG signal, cortisol secretion, and catecholamine production, respectively. We observed enhanced EEG signals, elevated cortisol levels and increased adrenaline productions. A group effect on cortisol output was revealed showing higher cortisol peak levels in the Mars520 group as compared to the control group, suggesting that HPA axis was to a certain extent more activated in the subjects who had chronic stress experience.

Abstract Free cortisol as measured in saliva increases markedly following awakening. It is not clear, however, whether this is truly a stress-neuroendocrine response to awakening or a manifestation of the hypothalamic-pituitary-adrenal (HPA) circadian cycle. We investigated whether the awakening cortisol response can be generated in the middle of nocturnal sleep, when secretory activity in the HPA axis is low. In a within subject design, salivary cortisol response was measured under three different awakening conditions: (1) awakening at the normal morning awakening time; (2) awakening four hours prior to normal awakening time, and (3) awakening the following morning after interrupted sleep. The overall main effect was a linear increase in free cortisol following awakening with no significant interaction with awakening condition. Cortisol levels, as determined by area under the cortisol curve calculated with reference to zero, did differ by awakening condition. The two morning awakening conditions were comparable but values were lower for night awakening. Area under the curve change (calculated with reference to the first awakening cortisol base value), however, did not distinguish the three awakening conditions. We conclude from these data that there is a clear free cortisol response to awakening for both nocturnal and morning awakening although the absolute levels produced are lower for nocturnal awakening when basal cortisol is low. Nocturnal interruption of sleep did not affect the subsequent morning response.

Recent studies have shown that cortisol levels rapidly increase within the first 30 minutes after awakening. This response is rather robust over weeks or months and is altered by chronic stress and burnout. The present study investigated to what extent the cortisol response to awakening relates to responses following hCRH, ACTH(1-24), or psychosocial stress challenges in 22 healthy subjects. Furthermore, a 12-hour circadian cortisol profile was obtained to compare the morning response with cortisol levels obtained throughout the day. Results show that the morning cortisol response was of similar magnitude to that following injection of 1 microg/kg h-CRH or exposure to a brief psychosocial stressor (TSST). All of these were significantly smaller compared to maximal stimulation of the adrenal cortex by ACTH(1-24). Correlation analyses revealed that the morning cortisol response was closely related only to the cortisol response following 0.25 mg ACTH(1-24) (r=0.63, p=0.002). We conclude that the morning cortisol response to awakening can provide important information on the (re)activity of the HPA axis in addition to more 'traditional' methods like hCRH or Synacthen challenge tests. The sensitivity/capacity of the adrenal cortex appears to play a crucial role for the magnitude of cortisol responses observed after awakening.

Cortisol production is increased during stress, and the actions of cortisol on receptors in the brain and other body organs are involved in allostasis, the process of adaptation to stress, as well as in allostatic load, the wear and tear associated with excessive exposure to cortisol. Using data from a community-based longitudinal study of older men and women, aged 70–79 yr, we tested the hypothesis that exposure to increasing levels of cortisol is associated with declines in memory performance. Associations between 12-h urinary free cortisol excretion and performance on tests of memory (delayed verbal recall and spatial recognition), abstraction, and spatial ability were examined. Among the women, greater cortisol excretion was associated with poorer baseline memory performance, independent of socio-demographic, health status, health behavior, and psychosocial characteristics. Moreover, women who exhibited increases in cortisol excretion over a 2.5-yr follow-up period were more likely to show declines in memory performance. By contrast, women who experienced declines in cortisol exhibited improvements in memory performance. No significant associations were found among the men. The results for the women suggest that decrements in memory performance associated with increases in cortisol may not represent irreversible effects, as declines in cortisol were associated with improvements in memory.

Human life is not without stressful challenges. These challenges may be even needed to fully exploit one’s potential, and not only include negative experiences in case of the loss of a loved significant other but also be positively colored, such as moving to a new job and trying to meet high-set expectations. We have been endowed with biobehavioral mechanisms to deal with such challenges. One of these mechanisms is the hypothalamus–pituitary–adrenal (HPA)-axis which is a central component of the body’s neuroendocrine response to stress. The hypothalamus secretes corticotropin-releasing hormone (CRH), which in turn stimulates the release of adrenocorticotropic hormone (ACTH) in the anterior pituitary. ACTH in turn stimulates the adrenal cortex to secrete cortisol. Cortisol is known as the major end product of the HPA-axis in humans [1]. Yet, activity of the HPA-axis does not end with the production of cortisol. The HPA-axis is controlled by negative feedback regulation that tends to normalize secretion of cortisol [1]. Elevated cortisol levels reduce ACTH levels as a consequence of negative feedback regulation, followed by a reduction in cortisol levels; in case of reduced cortisol levels, there is less negative feedback regulation at the pituitary, followed by an elevation in ACTH levels [2]. In normal nonstressful situations, cortisol secretion follows a circadian rhythm characterized by high levels in the morning followed by a decrease throughout the rest of the day. Generally, cortisol levels rise in about half an hour after awakening, which is known as the cortisol awakening response (CAR). The CAR is probably related to the

EFFECTS OF CORTISOL ON PHYSICAL AND PSYCHOLOGICAL ASPECTS OF THE BODY AND EFFECTIVE WAYS BY WHICH ONE CAN REDUCE STRESS Preethi Kandhalu B S J O ver the past years, reports of increased stress levels in millennials have been on the rise; Stress in America, a study, from the American Psychological Association found “half of all millennials are so stressed out that they can’t sleep at night, and 39 percent of millennials have stress levels that have increased in the past year” (Yandoli, 2013) and “On a 10-point scale, Americans ages 18-33 reported an average stress level of 5.4 compared to the national average of 4.9” (Kingkade, 2013). Consequently, there are a plethora of suggestions regarding ways to reduce stress – common tips include keeping a positive attitude, exercising and eating healthy (WebMD). A popular website also indicates that eating berries help combat stress since “Blueberries are naturally rich in vitamin C, which helps fight increased levels of cortisol, a stress hormone” 1 (Oz, 2010). Unfortunately, for most people, it is difficult to evaluate whether such tips are effective stress reducers. The aim of this article is to explain why stress exists. The cortisol hormone, i.e. “stress hormone” that’s secreted by the Hypothalamic-Pituitary-Adrenal (HPA) affects our body in both physical and mental ways that can be detrimental to our overall health. Some of the effects of stress can be due to our genes, while some effects can be due to external environmental factors. However, there do exist effective ways by which one can reduce cortisol levels. I n order to understand why we feel stressed, it is important to understand the mechanism of the Hypothalamic-Pituitary-Adrenal (HPA) axis, an axis (“Hypothalamic–pituitary–adrenal axis”). In the first step of the process, the hypothalamus contains neuroendocrine neurons that synthesize proteins, which act as hormones when released. While some hormones target distant tissues, some hormones – including vasopressin and corticotropin releasing hormone (CRH) – are released in the blood circulation of the axis for delivery to the pituitary gland. The CRH is received by the anterior pituitary gland, which in turn secretes Adrenocorticotropic Hormone (ACTH) within the blood circulation of the axis. ACTH further Fig 1. HPA Mechanism acts on the two of the three zones of the adrenal gland – zona fasciculate and the zona reticularis – this action leads to the secretion of glucocorticoids (which mainly consists of cortisol in humans) among other hormones (Mitrovic). Also, 90% of the cortisol is eventually “S ome ailments caused by increased levels in cortisol include a suppressed immune system , insomnia , severe mood swings , depression and severe hypotension ” along our brain that secretes cortisol. The hormones produced by the hypothalamus results in a cascade of events down the HPA axis which ultimately leads to the secretion of cortisol from the adrenal gland bound by proteins, whereas 10% of the free cortisol is unbound, and therefore biologically active – this free cortisol creates a negative feedback loop whereby it binds to hypothalamus and the pituitary gland to inhibit secretion of CRH and ACTH (Mitrovic). Scientific experiments done to determine correlation between Vitamin E and C levels, and cortisol levels actually suggest that cortisol production did not change with different concentrations of Vitamin E and C. In other words, blueberries do not fight increased levels of cortisol. (Montalvo, Diaz, Galdames, Andres & Larrain, 2011) 14 • B erkeley S cientific J ournal • S tress • F all 2013 V olume 18 • I ssue 1

Epidemiological studies have observed that psychosocial stress, for example, by unemployment, low socioeconomic status, or work stress, increases the risk of cardiovascular events.1 The pathophysiological basis of this association is poorly understood. Restraint stress, which is an experimental model for psychosocial stress, is characterized by the activation of the sympathetic nervous system involving the fast release of epinephrine and norepinephrine and the hypothalamic-pituitary-adrenal axis, resulting in a slow but sustained increase in circulating glucocorticoids.2 Both neuroendocrine axes elicit multiple and complex responses, aiming to protect the threatened organism. As yet, there is little and mixed epidemiological evidence about which of these pathways is relevant for the pathogenesis of cardiovascular diseases.3–6 Diurnal and other intraindividual variation of cortisol and catecholamine plasma concentrations make the design of meaningful observational studies difficult. More recently, measurements of cortisol in saliva or urine found positive associations between cortisol and risk of incident coronary events.5,6 Elevated cortisol levels in plasma or saliva have also been associated with increased blood pressure, diabetes mellitus, hyperglycemia, hypertriglyceridemia, and central adiposity. However, these associations have been questioned by 2 recent population studies that did not find any significant association of cortisol awakening response, evening cortisol, cortisol decline across the waking day, total cortisol output, and cortisol after dexamethasone suppression with metabolic syndrome or its individual components.7,8 Article, see p 1459 In addition to their importance of mobilizing stored energy and maintaining vascular tone during stress, glucocorticoids limit their own production by negative feedback inhibition, primarily via inhibiting the hypothalamic release of cortisol-releasing factor and the release of adrenocorticotropic hormone in the pituitary gland.2 Because cholesterol is a precursor of steroidogenesis, regulation of cholesterol metabolism is another potential target of glucocorticoid release in psychosocial stress. In this issue of …

This study examined the effect of chronic stress associated with unemployment on the magnitude of salivary cortisol excretion, on the diurnal rhythm of cortisol, and on cortisol reactivity to acute naturalistic stressors using Experience Sampling Methodology (ESM). Employed (N = 60) and unemployed (N = 60) subjects were studied for 2 days. Subjects were beeped 6 times per day by a preprogrammed wristwatch to assess acute stressors; 25 minutes after each ESM-beep, subjects were beeped a second time for saliva samples. The groups did not differ in their overall cortisol excretion or in cortisol reactivity to acute daily stressors. Compared to employed subjects, unemployed subjects had a diurnal pattern of cortisol excretion with relatively higher morning and lower evening levels. Subjects' daily activities and their locations were associated with diurnal rhythm differences.

Dysfunctional regulation of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as an important biological mechanism underlying stress-related diseases; however, a better understanding of the interlinked neuroendocrine events driving the release of cortisol by this stress axis is essential for progress in preventing or halting irreversible development of adverse HPA-function. We aimed to investigate basal HPA-activity in a normal population in late adolescence, the time of life believed to overlap with HPA-axis maturation and establishment of a lasting set point level of HPA function. A total of 1258 participants (mean age 16.6 years) recruited from the Western Australian Pregnancy (Raine) Cohort provided fasting morning blood and saliva samples for basal HPA activity assessment. Irrespective of gender, linear regression modelling identified a positive correlation between the main components of the HPA-cascade of events, ACTH, total cortisol and free cortisol in saliva. Corticosteroid binding globulin (CBG) was inversely associated with free cortisol in saliva, an effect most clearly observed in boys. ACTH levels were lower, but cortisol levels were higher in girls than in boys. Girls may also be exposed to more bioactive cortisol, based on higher average free cortisol measured in saliva at awakening. These relatively higher female free cortisol levels were significantly reduced by oral contraceptive use, eliminating the gender specific difference in salivary cortisol. Free plasma cortisol, calculated from total circulating cortisol and CBG concentrations, was also significantly reduced in girls using oral contraceptives, possibly via an enhancing effect of oral contraceptives on blood CBG content. This study highlights a clear gender difference in HPA activity under non-stressful natural conditions. This finding may be relevant for research into sex-specific stress-related diseases with a typical onset in late adolescence. (C) 2012 Elsevier Ltd. All rights reserved.

STUDIES show age-related changes in the pattern of cortisol release over the day (1,2). Cortisol is the final peripheral output of the hypothalamic–pituitary–adrenal axis, a major stress response system, and together with the sympathetic nervous system is responsible for changes in metabolic and immune function in response to internal or environmental stressors. Cortisol follows a circadian rhythm regulated by the biological clock in the suprachiasmatic nucleus of the hypothalamus. Normally, cortisol levels peak in the morning just after habitual awakening time and then gradually decrease throughout the day to a nadir at night. Cortisol diurnal rhythms allow healthy adaptation to the environment and proper daytime functioning. With age, the ability to synchronize internal circadian rhythms with the external environment decreases. This may be due to a physiological decline in suprachiasmatic nucleus function that potentially affects the regulation of behavioral and biological circadian processes (3–6), decreased daytime engagement in vocational and social activities, and/or increased medical burden related to aging. Although aging has been associated with higher basal cortisol levels (1,2,7), a raised cortisol awakening response (CAR [7]), and flatter diurnal slopes (7), it has been associated with decreased reactivity of cortisol levels to an experimental stress task (1). Increases in cortisol levels following a stressor are adaptive and help mobilize the individual to adequately cope with the stressor, whereas chronically low levels of cortisol (ie, hypocortisolism) have been associated with an inability to mobilize energetically to face a stressor and are common in exhaustion states and chronic fatigue syndrome (8). On the other hand, chronically elevated levels are maladaptive and deleterious to health and have been associated with poor sleep and a variety of psychiatric conditions (eg, depression [9]) and medical conditions (eg, obesity, diabetes, cardiovascular disease [10,11]). To our knowledge, there are no studies of the relationship between cortisol levels and health outcomes among older adults undergoing inpatient rehabilitation following an injury or illness. Patients in post-acute rehabilitation settings have generally been exposed to a long-term stressor that may alter basal cortisol levels (ie, the event that led to their need for rehabilitation, such as recovery from hip fracture). In addition, rehabilitation therapies may represent an acute stressor (eg, physical therapy, occupational therapy) that may lead to a temporary adaptive increase in cortisol levels. We examined the relationship between diurnal patterns of cortisol levels and functional outcomes in a subsample (n = 32) of participants in the larger study. The primary objective of the present study was to investigate whether there was a relationship between daytime cortisol levels and change in functional status between admission and discharge from post-acute rehabilitation. We also explored feasibility and methodological considerations associated with measuring salivary cortisol levels in this patient group.

Survival of seal pups may be affected by their ability to respond appropriately to stress. Chronic stress can adversely affect secretion of cortisol and thyroid hormones, which contribute to the control of fuel utilisation. Repeated handling could disrupt the endocrine response to stress and/or negatively impact upon mass changes during fasting. Here we investigated the effects of handling regime on cortisol and thyroid hormone levels, and body mass changes, in fasting male and female grey seal pups (Halichoerus grypus). Females had higher thyroid hormone levels than males throughout fasting and showed a reduction in cortisol midway through the fast that was not seen in males. This may reflect sex-specific fuel allocation or development. Neither handling frequency nor cumulative contact time affected plasma cortisol or thyroid hormone levels, the rate of increase in cortisol over the first five minutes of physical contact or the pattern of mass loss during fasting in either sex. The endocrine response to stress and the control of energy balance in grey seal pups appear to be robust to repeated, short periods of handling. Our results suggest that routine handling should have no additional impact on these animals than general disturbance caused by researchers moving around the colony.

3 studies of adrenocortical activity in healthy 9-month-old infants were conducted to examine unanticipated results obtained in previous research. In the first study, morning naps were examined and found to be associated with significant decreases in salivary cortisol. These decreases were followed by a significant return to prenap cortisol concentrations. In the second study, riding for 40 min in the car was also shown to significantly lower salivary cortisol concentrations. This effect was obtained both for infants who did and who did not sleep during the car trip. In the third study, the effect of 30 min of maternal separation in the laboratory on salivary cortisol was compared to the effect of 30 min of play with mother present. Separation resulted in significantly higher salivary cortisol concentrations as compared to play with mother present. In general, correlations between cortisol and behavior were found to be nonsignificant under conditions that did not produce stress elevations in cortisol, while less positive, more distressed behaviour was significantly correlated with cortisol under separation or stress conditions. Language: en

The possible association between stress-related exhaustion and reduced activity in the hypothalamo-pituitary-adrenal (HPA) axis is increasingly in focus. The aim of the present study was to examine whether exhaustion measured in a non-patient population is associated with alterations in diurnal cortisol profile. The study population included 78 working individuals. The study group was dichotomised into exhausted and non-exhausted groups by means of the SF-36 vitality scale. Salivary cortisol was measured at three times during 1 workday: at awakening, 30min after awakening, and in the evening. The results showed that diurnal cortisol variation was significantly reduced in exhausted individuals. The difference in cortisol variation was mainly due to lowered morning cortisol in the exhausted group. Differences in cortisol levels at each sampling time or in mean diurnal output of cortisol were not statistically significant. The results would support the notion that exhaustion is associated with HPA axis hypoactivity as assessed by salivary cortisol. Furthermore, the SF-36 vitality provides a measure of exhaustion that may be useful in epidemiological studies in order to explore long-term health effects of stress-related exhaustion.

Hypersecretion of cortisol is associated with depression. Because corticosterone may show greater responsiveness than cortisol to exogenous ACTH in depression and it has behavioural effects in rodents, we determined whether depression is also associated with hypersecretion of corticosterone. Both cortisol and corticosterone were significantly elevated in depression, with greatest differences from control subjects during the afternoon and evening. The ratio of corticosterone/cortisol was constant and similar throughout the day in both depressed patients and controls. We conclude that there is no disproportionate endogenous hypersecretion of corticosterone in depression.

A distinct rise in cortisol levels that occurs after morning awakening is increasingly used as an indicator of adrenocortical activity which is associated with different pathologies. Although it was previously assumed that the transition from sleep to wake is essential for the occurrence of the cortisol morning rise, this has never been tested. Here, we examined 16 healthy young men (20-33 yrs) between 2300 and 0800 h under sleep laboratory conditions. Serum cortisol and plasma adrenocorticotropin (ACTH) as well as salivary cortisol levels (after subjects were woken up at 0700 h) were repeatedly assessed. In a supplementary study condition, salivary cortisol levels in the first hour after awakening were measured at the subjects' home on two consecutive days. Comparison of pre- and post awakening measurements revealed significantly steeper increases in cortisol and ACTH after awakening. The rise in cortisol upon awakening under laboratory conditions did not significantly differ from that observed at home. We conclude that the cortisol increase after awakening is a response to morning awakening that is distinct from the circadian rise in hypothalamo-pituitary-adrenal (HPA) activity in the morning hours. Although the cortisol awakening response is modulated by circadian influences, it primarily reflects phasic psychophysiological processes specific to the sleep-wake transition.

Cortisol, the primary glucocorticoid in humans, is intimately involved in the regulation of such varied and critical biological processes as emotion, cognition, reward, immune functioning, and energy utilization. A persistent increase in cortisol concentration as a result of chronic intoxication could therefore result in alcohol-related disorders such as sleep disruption, cognitive deficits, diabetes, and mood disturbances. Although moderate levels of acute alcohol ingestion are reported to produce an increase in cortisol levels, it is uncertain whether cortisol remains persistently increased during long-term chronic intoxication.Salivary cortisol and breath alcohol concentrations (BAC) were obtained on 73 subjects with primary alcohol dependence on initial presentation for treatment and 22 alcohol-dependent subjects participating in a residential treatment program.Both intoxicated alcohol-dependent subjects (n = 38) and nonintoxicated subjects in acute alcohol withdrawal (n = 30) demonstrated significantly increased salivary cortisol concentrations compared with abstinent subjects (n = 27; p0.001). Nonintoxicated subjects in acute withdrawal demonstrated significantly increased salivary cortisol concentrations compared with highly intoxicated subjects (BAC100 mg/dl) but were similar to subjects with lower levels of intoxication (BAC, 10-100 mg/dl).Chronic alcohol-dependent subjects experience continuously increased concentrations of cortisol during both intoxication and withdrawal. Increased levels of cortisol during chronic intoxication seem to progressively increase with the onset of withdrawal. This suggests a daily cycle of hypercortisolemia during the active drinking phase, with further increases on the cessation of drinking and the emergence of withdrawal symptoms. Persistently increased levels of cortisol may extract a costly allostatic load, resulting in significant central nervous system and peripheral organ morbidity.

The effect of light on the morning-cortisol peak in humans was investigated in fourteen healthy men by exposing them to darkness and to light of 800 lux during a 1-h period on two subsequent mornings. In the early morning, we demonstrated a temporary increase of salivary cortisol levels after awakening, while light exposure resulted in a +/- 35% further increase in cortisol levels. Cortisol levels 20 and 40 min after waking were significantly higher during 800 lux exposure than during darkness. In order to investigate the time-dependency, the experiment was repeated in the late evening. In the evening, light had no effect on cortisol levels. These results demonstrate that light conditions in the early morning have a strong impact on the morning-cortisol peak, but that evening cortisol levels are unaffected by light. The possible role of the circadian pacemaker as mediator of the light effect on cortisol level is discussed.

The hypothalamic-pituitary-adrenal axis is characterized by a marked circadian cycle with heightened activity in the morning. This is synchronized to awakening such that free cortisol increases two to three fold in the first thirty to forty five minutes following awakening -- the awakening cortisol response. It has been suggested that this activity, by mobilizing energy reserves prepares the body for the metabolic demands of the day. Similar arguments are applied to the cortisol response to psychological challenge. Paradoxically the cortisol response to a psychosocial stressor is abrogated in fasted individuals with low blood glucose. Also cortisol response to a psychosocial stressor is positively correlated to blood glucose levels after glucose load. We examined if the same relationship applies to the awakening cortisol response. There was no correlation between the cortisol response and awakening blood glucose levels. Moreover a group with mean blood glucose at the bottom of the euglycemic range, identified by split at the median for glucose level upon awakening, showed no deficit in cortisol response. Hence the physiology of the awakening response differs to that of a psychological stress response. These data challenge the view that an oxidisable substrate for energy metabolism is permissive for cortisol responses. In addition the present findings do not support a predominantly gluconeogenic role for morning cortisol activation.

The present study was designed to elucidate the effect of depressive symptomatology on the cortisol response to strenuous exercise. Thirteen healthy, post-menopausal women participated in this study. The results show that acute bicycle exercise activates the hypothalamic-pituitary-adrenal (HPA) axis resulting in rapid increases in plasma cortisol. Concerning the effect of depressive symptomatology on cortisol release during physical performance, we found a trend toward a negative relation between the level of depression and the change in cortisol measured after termination of the exercise, but it failed to reach statistical significance, probably due to the small sample size. Interestingly, we found a significant negative correlation between basal cortisol levels and cortisol release to the exercise protocol. Although this finding is preliminary, it seems to suggest that a sustained activation of the HPA axis may coincide with an adrenal insufficiency in response to physical performance of post-menopausal women.

SUMMARY Effects of past, current, and anticipated naturalistic daily stressors and of affect on salivary cortisol levels were examined. Participants (120) reported on stressors and affect 6:day in response to a preprogrammed wristwatch. Twenty min after each assessment they took a sample of saliva for cortisol analysis. Both the experience of a current stressor and anticipating a stressor were associated with increased salivary cortisol levels. Average increases in cortisol were relatively low, but inter-individual variability in this response existed. Stressors also were associated with lower positive affect and higher negative affect. Negative affect was associated with higher cortisol levels and positive affect was associated with lower cortisol levels. Daily stressors were not significant predictors of cortisol secretion when affect was controlled. Momentary assessment of daily stressors and of salivary cortisol proved to be a useful tool for examining psychoendocrinological processes in the natural environment. 1998 © Elsevier Science Ltd. All rights reserved.

Sleep curtailment constitutes an increasingly common condition in industrialized societies and is thought to affect mood and performance rather than physiological functions. There is no evidence for prolonged or delayed effects of sleep loss on the hypothalamo-pituitary-adrenal (HPA) axis. We evaluated the effects of acute partial or total sleep deprivation on the nighttime and daytime profile of cortisol levels. Plasma cortisol profiles were determined during a 32-hour period (from 1800 hours on day 1 until 0200 hours on day 3) in normal young men submitted to three different protocols: normal sleep schedule (2300-0700 hours), partial sleep deprivation (0400-0800 hours), and total sleep deprivation. Alterations in cortisol levels could only be demonstrated in the evening following the night of sleep deprivation. After normal sleep, plasma cortisol levels over the 1800-2300-hour period were similar on days 1 and 2. After partial and total sleep deprivation, plasma cortisol levels over the 1800-2300-hour period were higher on day 2 than on day 1 (37 and 45% increases, p = 0.03 and 0.003, respectively), and the onset of the quiescent period of cortisol secretion was delayed by at least 1 hour. We conclude that even partial acute sleep loss delays the recovery of the HPA from early morning circadian stimulation and is thus likely to involve an alteration in negative glucocorticoid feedback regulation. Sleep loss could thus affect the resiliency of the stress response and may accelerate the development of metabolic and cognitive consequences of glucocorticoid excess.

Elevated cortisol is found in many diseases, including infectious, aging-related, depression and depression-associated conditions; even in some with no known origin, and no known therapy. While it was initially thought that 'high cortisol' is the result of these diseases, there is mounting evidence to the contrary, namely, that high cortisol actually plays a major role in inducing them, opening the possibility that anti-cortisol drugs might represent a new beneficial therapy. Evidence is here presented, showing that the use of anti-cortisol drugs has already induced beneficial results in conditions ranging from AIDS to depression. A main reason for not realizing the major role played by cortisol is due to a defective interpretation of cortisol results. If cortisol is within normal range of 0800 h or 1700 h, it has been considered normal, without realizing that swings, sometimes at immunosuppressive levels, might occur during its 24 h circadian rhythm. We suggest that a first step toward unveiling the role of cortisol in diseases would be to develop a standardized cortisol circadian rhythm chart that would show normal levels at any time during a 24 h period, enabling a more accurate comparison with cortisol values obtained under pathological conditions.

1. 1. The immunosuppressive effects of drugs such as alcohol or hormones such as cortisol may be age-related. To test this hypothesis, the authors investigated the in vitro effects of ethanol (EtOH) and cortisol on Natural Killer (NK) cell activity of lymphocytes from normal cord blood in comparison with that of lymphocytes from normal adult peripheral blood. 2. 2. K562, an erythroleukemia cell line, was used as a target in a 4 hr 51 Cr release assay. 3. 3. Ethanol at 0.3% (V/V) and cortisol at 0.05, 0.1 and 0.2 μg/ml concentrations, added directly to a mixture of effector and target cells significantly suppressed the NK activity of cord blood lymphocytes in a dose dependent fashion, whereas similar concentrations of either EtOH or cortisol did not manifest significant immunoregulatory effects on NK cell activity of normal adult lymphocytes. 4. 4. Pre-treatment of the target with either EtOH or cortisol for 4 hours did not affect cytotoxicity. Inhibition of cytotoxicity was also not due to direct toxicity of effector cells because lymphocytes treated with either EtOH or cortisol showed normal 51 Cr release and their viability was comparable to that of untreated control cells. 5. 5. This suggests a selective inhibitory effect of EtOH and cortisol on NK activity of neonatal lymphocytes that may be of clinical significance.

The relationship between the temporal organization of cortisol secretion and sleep structure is controversial. To determine whether the cortisol profile is modified by 4 hours of sleep deprivation, which shifts slow-wave sleep (SWS) episodes, 12 normal men were studied during a reference night, a sleep deprivation night and a recovery night. Plasma cortisol was measured in 10-minute blood samples. Analysis of the nocturnal cortisol profiles and the concomitant patterns of sleep stage distribution indicates that the cortisol profile is not influenced by sleep deprivation. Neither the starting time of the cortisol increase nor the mean number and amplitude of pulses was significantly different between the three nights. SWS episodes were significantly associated with declining plasma cortisol levels (p less than 0.01). This was especially revealed after sleep deprivation, as SWS episodes were particularly present during the second half of the night, a period of enhanced cortisol secretion. In 73% of cases, rapid eye movement sleep phases started when cortisol was reflecting diminished adrenocortical activity. Cortisol increases were not concomitant with a specific sleep stage but generally accompanied prolonged waking periods. These findings tend to imply that cortisol-releasing mechanisms may be involved in the regulation of sleep.

It has been shown that, in the rat, physical stress decreases pineal melatonin levels at night, whereas it increases melatonin production during the day. We have demonstrated that nighttime physical exercise is able to blunt the nocturnal surge of plasma melatonin in healthy subjects. Since this effect might be mediated by exercise-induced cortisol secretion from the adrenal gland, in the present investigation we studied the relationship between cortisol and melatonin responses to nighttime physical stress in six healthy men, aged 28-33 yr. The physical stress consisted of bicycling on a bicycle ergometer at 50% of personal maximum work capacity (MWC), followed by another 10 min of bicycling at 80% of MWC. According to our previous data, physical exercise performed between 2240 h and 2300 h significantly reduced the nocturnal surge of plasma melatonin and increased the levels of cortisol. The surge in plasma cortisol preceded the decrease in plasma melatonin concentration. These findings suggest a temporal relationship between plasma cortisol and melatonin responses to physical stress; the causal nature of this relationship remains to be elucidated.

The relationship between the performance of post-feeding stereotypic behaviour and plasma cortisol levels and the effect of prevention of stereotypic behaviour on plasma cortisol levels were studied in chronically restrained sows. In experiment 1 sows classified as high or low stereotypers on the basis of time spent manipulating chain and behaviour directed to the nipple drinker were found not to differ in plasma cortisol levels. Removing the chain and nipple drinkers also did not affect cortisol concentrations of either group. In experiment 2 detailed recordings were made by an automatic logging system of two major categories of stereotypy; chain manipulation and drinking. There were large individual differences in levels of both chain manipulation and drinking. Both activities showed a similar diurnal pattern, but average levels across individuals were not correlated. Both activities showed a continuous distribution across individuals and therefore a correlational rather than factorial analysis was used. Chain manipulation was not correlated to cortisol concentrations on any of the control days and removing the chain for one day (experiment 2A) or for seven days (experiment 2B) was also not accompanied by increased cortisol levels. However individuals showed a consistent cortisol response to chain removal as indicated by correlations between treatment days. Drinking showed a tendency to be negatively correlated to cortisol concentrations on control days. Long-term chain removal was accompanied by an increase in average drinking that showed a non-significant tendency to be negatively correlated to plasma cortisol on treatment days and thus may explain part of the consistency of response to chain removal. The lack of correlation between chain manipulation and plasma cortisol suggests that this activity does not serve to reduce plasma cortisol in chronically restrained sows. The relationship between drinking and cortisol need not necessarily reflect the coping capacity of this behaviour but may be a physiological consequence of the large amounts of water ingested.