Cortisol Awakening Response Is Linked to Disease Course and Progression in Multiple Sclerosis

Objectives

Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis has frequently been reported in multiple sclerosis (MS). So far, HPA axis function in MS has predominantly been studied under pharmacological stimulation which is associated with a series of methodological caveats. Knowledge of circadian cortisol patterns and cortisol awakening response (CAR) is still limited.

Methods

A total of 77 MS patients (55 relapsing-remitting MS (RRMS)/22 secondary-progressive MS (SPMS)) as well as 34 healthy control (HC) subjects were enrolled. Diurnal cortisol release was assessed by repeated salivary cortisol sampling. Neurological disability was rated by the Kurtzke’s Expanded Disability Status Scale (EDSS). Depressive symptoms and perceived stress were assessed by self-report measures.

Results

RRMS but not SPMS patients differed in circadian cortisol release from HC subjects. Differences in cortisol release were restricted to CAR. Treated and treatment naïve RRMS patients did not differ in CAR. In a RRMS follow-up cohort (nine months follow-up), RRMS patients with EDSS progression (≥0.5) expressed a significantly greater CAR compared to HC subjects. RRMS patients with a stable EDSS did not differ from HC subjects. Neither depressive symptoms nor perceived stress ratings were associated with CAR in RRMS patients. In a step-wise regression analysis, EDSS at baseline and CAR were predictive of EDSS at follow-up (R² = 67%) for RRMS patients.

Conclusions

Circadian cortisol release, in particular CAR, shows a course specific pattern with most pronounced release in RRMS. There is also some evidence for greater CAR in RRMS patients with EDSS progression. As a consequence, CAR might be of predictive value in terms of neurological disability in RRMS patients. The possible role of neuroendocrine-immune interactions in MS pathogenesis is further discussed.     

Behavioral and cortisol responses to repeated capture and venipuncture in Cebus apella

Eight capuchins were trained in a capture and venipuncture procedure. Samples taken immediately following capture indicated that subjects experienced rising cortisol levels over the first 5 weeks of training followed by a return to baseline (equivalent to day 1 levels) in the sixth and seventh weeks. After 7 weeks, samples taken 60 min after initial capture revealed that behaviorally habituated animals exhibited significantly lower cortisol levels in response to venipuncture as opposed to naive and experienced but nonbehaviorally habituated subjects. © 1996 Wiley-Liss, Inc.     

Do social disadvantage and early family adversity affect the diurnal cortisol rhythm in infants? The Generation R Study

Dysregulation of diurnal cortisol secretion patterns may explain the link between adversities early in life and later mental health problems. However, few studies have investigated the influence of social disadvantage and family adversity on the hypothalamic-pituitary-adrenal (HPA) axis early in life. In 366 infants aged 12-20 months from the Generation R Study, a population-based cohort from fetal life onwards, parents collected saliva samples from their infant at 5 moments over the course of 1 day. The area under the curve (AUC), the cortisol awakening response (CAR) and the diurnal cortisol slope were calculated as different composite measures of the diurnal cortisol rhythm. Information about social disadvantage and early adversity was collected using prenatal and postnatal questionnaires.We found that older infants showed lower AUC levels; moreover, infants with a positive CAR were significantly older. Both the AUC and the CAR were related to indicators of social disadvantage and early adversity. Infants of low income families, in comparison to high income families, showed higher AUC levels and a positive CAR. Infants of mothers who smoked during pregnancy were also significantly more likely to show a positive CAR. Furthermore, infants of mothers experiencing parenting stress showed higher AUC levels. The results of our study show that effects of social disadvantage and early adversity on the diurnal cortisol rhythm are already observable in infants. This may reflect the influence of early negative life events on early maturation of the HPA axis.     

When does stress end? Evidence of a prolonged stress reaction in shiftworking truck drivers

This study aimed to analyze individual cortisol levels in relation to work conditions, sleep, and health parameters among truck drivers working day shifts (n = 21) compared to those working irregular shifts (n = 21). A total of 42 male truck drivers (39.8 (+/-) 6.2 yrs) completed questionnaires about sociodemographics, job content, work environment, health, and lifestyle. Rest-activity profiles were measured using actigraphy, and cardiovascular blood parameters were collected. Salivary cortisol samples were obtained: (i) at waking time, (ii) 30?min after waking, and (iii) at bedtime, during both one workday and one day off from work. Irregular-shift workers, compared to day-shift workers, showed significantly higher waist-hip ratio, very-low-density lipoprotein (VLDL) cholesterol, tiredness after work, years working as a driver, truck vibration, and less job demand (p < .05). High cortisol levels in irregular-shift workers were correlated with certain stressors, such as short sleep duration and low job satisfaction, and to metabolic parameters, such as total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), VLDL, and triglycerides. Day-shift workers had higher cortisol levels collected 30?min after waking (p = .03) and a higher cortisol awakening response (CAR; p = .02) during workdays compared to off days. Irregular-shift workers had higher cortisol levels on their off days compared to day-shift workers (p = .03). In conclusion, for the day-shift workers, a higher cortisol response was observed on workdays compared to off days. Although no direct comparisons could be made between groups for work days, on off days the irregular-shift workers had higher cortisol levels compared to day-shift workers, suggesting a prolonged stress response in the irregular-shift group. In addition, cortisol levels were correlated with stressors and metabolic parameters. Future studies are warranted to investigate further stress responses in the context of irregular work hours.     

Restoring the Salivary Cortisol Awakening Response Through Nasal Continuous Positive Airway Pressure Therapy in Obstructive Sleep Apnea

Partial and largely conflicting data are currently available on the interplay between obstructive sleep apnea (OSA) and hypothalamus-pituitary-adrenal axis (HPA) activity in adult obese men. This study was performed to evaluate the daily trajectories of salivary cortisol, specifically with respect to the salivary cortisol awakening response (CAR), a common method used to assess HPA axis activity. The main findings of this study were that adult male obese subjects who were newly diagnosed with severe OSA showed the following: (1) a flattening of the CAR; (2) levels of cortisol at awakening that were lower than those of the controls; and (3) maintenance of the physiological circadian activity of the HPA axis, with the highest hormone concentrations produced in the morning and the lowest in the evening. This study was also designed to investigate the effects of 3 and 6 mos of treatment with continuous airways positive pressure (CPAP). CPAP use resulted in a significant recovery of the sleep patterns disrupted by OSA; moreover, mild neuropsychological signs of depression and anxiety in severe OSA patients were concomitantly progressively improved by CPAP treatment. Furthermore, this study reports that 3 and 6 mos of CPAP therapy restored the presence of CAR and was able to significantly reduce the difference in the morning cortisol levels between the OSA and control groups. In conclusion, we report here that compared with obese nonapneic matched controls, OSA patients present a dysregulation of HPA axis activity, as shown by the flattening of the diurnal pattern of cortisol production in response to repeated challenge due to hypoxia and sleep fragmentation. This dysregulation was especially detectable in the first hour after awakening and restored after 3 and 6 mos of treatment with CPAP.     

Plasma acth and cortisol levels in depressed patients: Relation to dexamethasone suppression test

Blood samples collected from normal subjects and newly hospitalized depressed patients at 8 AM on the day before and at 8 AM and 4 PM the day after receiving dexamethasone, 1 mg orally at 11 PM, were analyzed for ACTH and cortisol. The mean plasma ACTH values of these two groups were not significantly different at any of the times, while the cortisol levels of the depressed patients were significantly higher than those of the normal subjects at 8 AM pre-dexamethasone (P<0.001). There was no correlation between plasma ACTH and cortisol values in either group. The cortisol responses to dexamethasone in depressed patients revealed two subgroups. In one subgroup, the cortisol was suppressed as much as in normal subjects, but in the other, cortisol levels were not suppressed. The post-dexamethasone ACTH rebounded at 4 PM in the latter subgroup to higher values than in the subgroup with suppressed cortisol levels and in the normal subjects. After dexamethasone, the ACTH values were negatively correlated with plasma cortisol only in the normal subjects (P<0.01), not in the depressed patients. These results indicate that ACTH levels do not account for the elevated cortisol and the failure of dexamethasone to suppress cortisol levels in some depressed patients.     

Cortisol reduces plasticity in the kitten visual cortex

We investigated the effect of elevated levels of cortisol on plasticity in the visual cortex of the cat. Animals were given daily injections of cortisol i.m. for 20 days starting around 35 days of age. After 10 days they were monocularly deprived, and after an additional 10 days recordings were made from the visual cortex to construct an ocular dominance histogram. The results were compared with those from normal animals of the same age, and with animals monocularly deprived for the same period but not treated with cortisol. Cortisol reduced the ocular dominance shift in a dose-dependent manner, but did not totally abolish it even at the highest doses used. Two other series of animals were recorded, one slightly later in the critical period and one slightly earlier, with care taken to give cortisol before the animals were exposed to light in the morning. In both cases, cortisol reduced the ocular dominance shift but did not abolish it. To interpret these results, we measured levels of plasma cortisol in normal cats of various ages. Average levels were fairly constant between birth and 12 months of age (0.5–1 μg/dl), and increased slightly after that, but there was a large variation between animals. Thus elevated levels of cortisol can have a substantial effect on plasticity in the visual cortex of the cat, but the decline of the critical period for plasticity between 6 weeks and 3–5 months of age does not seem to be due to a rise in cortisol levels during this time.     

Cortisol reduces plasticity in the kitten visual cortex.

We investigated the effect of elevated levels of cortisol on plasticity in the visual cortex of the cat. Animals were given daily injections of cortisol i.m. for 20 days starting around 35 days of age. After 10 days they were monocularly deprived, and after an additional 10 days recordings were made from the visual cortex to construct an ocular dominance histogram. The results were compared with those from normal animals of the same age, and with animals monocularly deprived for the same period but not treated with cortisol. Cortisol reduced the ocular dominance shift in a dose-dependent manner, but did not totally abolish it even at the highest doses used. Two other series of animals were recorded, one slightly later in the critical period and one slightly earlier, with care taken to give cortisol before the animals were exposed to light in the morning. In both cases, cortisol reduced the ocular dominance shift but did not abolish it. To interpret these results, we measured levels of plasma cortisol in normal cats of various ages. Average levels were fairly constant between birth and 12 months of age (0.5-1 microgram/dl), and increased slightly after that, but there was a large variation between animals. Thus elevated levels of cortisol can have a substantial effect on plasticity in the visual cortex of the cat, but the decline of the critical period for plasticity between 6 weeks and 3-5 months of age does not seem to be due to a rise in cortisol levels during this time.     

Acculturation, childhood trauma and the cortisol awakening response in Mexican-American adults

Exposure to chronic and traumatic stress has been associated with the dysregulation of crucial stress response systems. Acculturation has been associated with unique forms of chronic psychosocial stress. The purpose of this study was to examine the effects of exposure to early traumatic stress and acculturation on dysregulation of the cortisol awakening response (CAR) in Mexican-American adults. Salivary cortisol samples were collected at awakening and 30, 45, and 60 min thereafter, on two consecutive weekdays from 59 healthy Mexican-American adult males (26) and females (33), ages 18-38 years. Participants were assessed for level of acculturation and exposure to early trauma. Data were analyzed using a mixed effects regression model with repeated measures at four time points. Mixed effects regression results indicated a significant Early Trauma × Time interaction (p = .0029) and a significant Acculturation × Time interaction (p = .0015), after controlling for age and sex. Subsequent analyses of the interaction of Trauma × Acculturation × Time showed that more than minimal exposure to either risk factor was associated with attenuation of the awakening cortisol response (p = .0002). Higher levels of acculturation with greater Anglo-orientation were associated with attenuation of the CAR in Mexican-American adults. Both moderate and higher levels of exposure to early trauma were associated with an attenuated CAR. However, greater exposure to both risk factors was only incrementally worse than exposure to either one.     

When Does Stress End? Evidence of a Prolonged Stress Reaction in Shiftworking Truck Drivers

This study aimed to analyze individual cortisol levels in relation to work conditions, sleep, and health parameters among truck drivers working day shifts (n?=?21) compared to those working irregular shifts (n?=?21). A total of 42 male truck drivers (39.8?±?6.2 yrs) completed questionnaires about sociodemographics, job content, work environment, health, and lifestyle. Rest-activity profiles were measured using actigraphy, and cardiovascular blood parameters were collected. Salivary cortisol samples were obtained: (i) at waking time, (ii) 30?min after waking, and (iii) at bedtime, during both one workday and one day off from work. Irregular-shift workers, compared to day-shift workers, showed significantly higher waist-hip ratio, very-low-density lipoprotein (VLDL) cholesterol, tiredness after work, years working as a driver, truck vibration, and less job demand (p?<?.05). High cortisol levels in irregular-shift workers were correlated with certain stressors, such as short sleep duration and low job satisfaction, and to metabolic parameters, such as total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), VLDL, and triglycerides. Day-shift workers had higher cortisol levels collected 30?min after waking (p?=?.03) and a higher cortisol awakening response (CAR; p?=?.02) during workdays compared to off days. Irregular-shift workers had higher cortisol levels on their off days compared to day-shift workers (p?=?.03). In conclusion, for the day-shift workers, a higher cortisol response was observed on workdays compared to off days. Although no direct comparisons could be made between groups for work days, on off days the irregular-shift workers had higher cortisol levels compared to day-shift workers, suggesting a prolonged stress response in the irregular-shift group. In addition, cortisol levels were correlated with stressors and metabolic parameters. Future studies are warranted to investigate further stress responses in the context of irregular work hours. (Author correspondence: crmoreno@usp.br)     

Are Individuals' Nighttime Sleep Characteristics Prior to Shift‐Work Exposure Predictive for Parameters of Daytime Sleep after Commencing Shift Work?

This study aimed to examine prospectively whether individual nighttime sleep characteristics at baseline (prior to shift‐work exposure) are related to parameters of daytime sleep after commencing shift work. A longitudinal field study was carried out with novice police officers of the Dutch Police Force. A total of 26 subjects were examined at baseline before they entered shift work and re‐examined during follow‐up sessions after four and twelve months of shift‐work exposure. Wrist actigraphy and sleep diaries were used to study nocturnal sleep at baseline and daytime sleep after night shifts during follow‐up sessions. As outcome variables, estimated total sleep time, sleep efficiency, and subjective sleep quality were analyzed. Daytime total sleep time showed a 66 min decline during the first year of shift‐work exposure. Systematic inter‐individual differences were observed for daytime total sleep time and subjective sleep quality (explaining 53% and 38% of the variance, respectively), suggesting potential predictability of these sleep parameters. Although no predictors were found for daytime total sleep time, the subjective quality of nighttime sleep before the onset of shift work predicted 40% of the variance in the subjective quality of daytime sleep after commencing shift work. Follow‐up studies may reveal whether the subjective quality of baseline nighttime sleep also predicts long‐term overall tolerance for shift work.     

Differences in Salivary Alpha-Amylase and Cortisol Responsiveness following Exposure to Electrical Stimulation versus the Trier Social Stress Tests

Background

Cortisol is an essential hormone in the regulation of the stress response along the HPA axis, and salivary cortisol has been used as a measure of free circulating cortisol levels. Recently, salivary alpha-amylase (sAA) has also emerged as a novel biomarker for psychosocial stress responsiveness within the sympathetic adrenomedullary (SAM) system.

Principal Findings

We measured sAA and salivary cortisol in healthy volunteers after exposure to the Trier Social Stress Test (TSST) and electric stimulation stress. One hundred forty-nine healthy volunteers participated in this study. All subjects were exposed to both the TSST and electric stimulation stress on separate days. We measured sAA and salivary cortisol levels three times immediately before, immediately after, and 20 min after the stress challenge. The State (STAI-S) and Trait (STAI-T) versions of the Spielberger Anxiety Inventory test and the Profile of Mood State (POMS) tests were administered to participants before the electrical stimulation and TSST protocols. We also measured HF, LF and LF/HF Heart Rate Variability ratio immediately after electrical stimulation and TSST exposure. Following TSST exposure or electrical stimulation, sAA levels displayed a rapid increase and recovery, returning to baseline levels 20 min after the stress challenge. Salivary cortisol responses showed a delayed increase, which remained significantly elevated from baseline levels 20 min after the stress challenge. Analyses revealed no differences between men and women with regard to their sAA response to the challenges (TSST or electric stimulations), while we found significantly higher salivary cortisol responses to the TSST in females. We also found that younger subjects tended to display higher sAA activity. Salivary cortisol levels were significantly correlated with the strength of the applied electrical stimulation.

Conclusions

These preliminary results suggest that the HPA axis (but not the SAM system) may show differential response patterns to distinct kinds of stressors.     

Are individuals' nighttime sleep characteristics prior to shift-work exposure predictive for parameters of daytime sleep after commencing shift work?

This study aimed to examine prospectively whether individual nighttime sleep characteristics at baseline (prior to shift-work exposure) are related to parameters of daytime sleep after commencing shift work. A longitudinal field study was carried out with novice police officers of the Dutch Police Force. A total of 26 subjects were examined at baseline before they entered shift work and re-examined during follow-up sessions after four and twelve months of shift-work exposure. Wrist actigraphy and sleep diaries were used to study nocturnal sleep at baseline and daytime sleep after night shifts during follow-up sessions. As outcome variables, estimated total sleep time, sleep efficiency, and subjective sleep quality were analyzed. Daytime total sleep time showed a 66 min decline during the first year of shift-work exposure. Systematic inter-individual differences were observed for daytime total sleep time and subjective sleep quality (explaining 53% and 38% of the variance, respectively), suggesting potential predictability of these sleep parameters. Although no predictors were found for daytime total sleep time, the subjective quality of nighttime sleep before the onset of shift work predicted 40% of the variance in the subjective quality of daytime sleep after commencing shift work. Follow-up studies may reveal whether the subjective quality of baseline nighttime sleep also predicts long-term overall tolerance for shift work.     

The cortisol response to awakening in relation to different challenge tests and a 12-hour cortisol rhythm.

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.     

The biological clock modulates the human cortisol response in a multiplicative fashion

Human cortisol levels follow a clear circadian rhythm. We investigated the contribution of alternation of sleep and wakefulness and the circadian clock, using forced desynchrony. Cortisol levels were best described by a multiplication of a circadian and a wake-time component. The human cortisol response is modulated by circadian phase. Exposure to stress at an unnatural phase, as in shift work, is predicted to result in abnormal cortisol levels. Health of shift workers may therefore improve when stress is reduced at times when the clock produces high stress sensitivity.     

Cortisol levels in glucose-6-phosphate dehydrogenase deficiency.

The aim of the present study was to investigate cortisol levels under basal conditions and in response to ACTH stimulation in male patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. The study included 14 male controls and 12 patients with G-6-PD deficiency matched for age and race. Fasting blood samples were taken from all the subjects at rest, and 30, 60 and 120 min after the infusion of 0.25 mg of corticotropin for cortisol determination. The mean cortisol levels observed in the first hour after ACTH stimulation in the G-6-PD-deficient patients were significantly (p = 0.03) lower than in the control group. No significant differences were observed between patients and controls at rest, and in the second hour after stimulation. These data suggest that, in the adrenals, G-6-PD plays a role in the initial phase of cortisol production. However, 1 h after ACTH stimulation, G-6-PD probably is no longer rate limiting in the production of cortisol.     

Shiftwork duration and the awakening cortisol response among police officers

Police officers are required to work irregular hours, which induces stress, fatigue, and sleep disruption, and they have higher rates of chronic disease and mortality. Cortisol is a well-known "stress hormone" produced via activation of the hypothalamic-pituitary-adrenal axis. An abnormal secretion pattern has been associated with immune system dysregulation and may serve as an early indicator of disease risk. This study examined the effects of long- and short-term shiftwork on the cortisol awakening response among officers (n = 68) in the Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS) pilot study (2001-2003). The time each officer spent on day (start time: 04:00-11:59 h), afternoon (12:00-19:59 h), or night (20:00-03:59 h) shifts was summarized from 1994 to examination date to characterize long-term (mean: 14 ± 9 yrs) and short-term (3, 5, 7, or 14 days prior to participation) shiftwork exposures. The cortisol awakening response was characterized by summarizing the area under the curve (AUC) for samples collected on first awakening, and at 15-, 30-, and 45-min intervals after waking. Data were collected on a scheduled training or off day. The cortisol AUC with respect to ground (AUC(G)) summarized total cortisol output after waking, and the cortisol AUC with respect to increase (AUC(I)) characterized the waking cortisol response. Officers also completed the Center for Epidemiologic Studies Depression scale. Waking cortisol AUC values were lower among officers working short-term night or afternoon shifts than day shifts, with maximal differences occurring after 5 days of shiftwork. The duration of long-term shiftwork was not associated with the cortisol awakening response, although values were attenuated among officers with more career shift changes.     

Chronic Stress Induces a Hyporeactivity of the Autonomic Nervous System in Response to Acute Mental Stressor and Impairs Cognitive Performance in Business Executives

The present study examined the incidence of chronic stress in business executives (109 subjects: 75 male and 34 female) and its relationship with cortisol levels, cognitive performance, and autonomic nervous system (ANS) reactivity after an acute mental stressor. Blood samples were collected from the subjects to measure cortisol concentration. After the sample collection, the subjects completed the Lipp Inventory of Stress Symptoms for Adults and the Stroop Color-Word Test to evaluate stress and cognitive performance levels, respectively. Saliva samples were collected prior to, immediately after, and five minutes after the test. The results revealed that 90.1% of the stressed subjects experienced stress phases that are considered chronic stress. At rest, the subjects with chronic stress showed higher cortisol levels, and no gender differences were observed. No differences were found between the stressed and non-stressed subjects regarding salivary amylase activity prior to test. Chronic stress also impaired performance on the Stroop test, which revealed higher rates of error and longer reaction times in the incongruent stimulus task independently of gender. For the congruent stimulus task of the Stroop test, the stressed males presented a higher rate of errors than the non-stressed males and a longer reaction time than the stressed females. After the acute mental stressor, the non-stressed male group showed an increase in salivary alpha-amylase activity, which returned to the initial values five minutes after the test; this ANS reactivity was not observed in the chronically stressed male subjects. The ANS responses of the non-stressed vs stressed female groups were not different prior to or after the Stroop test. This study is the first to demonstrate a blunted reactivity of the ANS when male subjects with chronic psychological stress were subjected to an acute mental stressor, and this change could contribute to impairments in cognitive performance.     

Association of worse prognosis with an aberrant diurnal cortisol rhythm in patients with advanced lung cancer

A flatter diurnal rhythm of cortisol has been reported to be associated with early mortality in patients with metastatic breast cancer. The clinical stage of disease at the time of diagnosis and the patient's performance status (PS) are known to be important prognostic factors for lung cancer (LC) survival. The authors examined the relationship between diurnal cortisol rhythms and these prognostic factors in patients with advanced LC. Cortisol concentrations were measured in saliva samples collected from 52 patients (37 males/15 females) with advanced LC and from 56 healthy subjects (32 males/24 females) to characterize the diurnal cortisol rhythm, specifically the cortisol awakening response (CAR) and diurnal cortisol decline (DCD). Variations of CAR and DCD in the patients were analyzed according to their clinical disease stage and PS score, and the differences in CAR and DCD between patients and healthy controls were compared. The patient group showed significantly reduced diurnal cortisol secretory activity and rhythmicity, compared with healthy controls. When the patients were subgrouped according to their clinical disease stage, patients with stage 4 disease showed significantly reduced CAR and flatter DCD compared with the healthy controls. However, the CAR and DCD in patients with stage 3a and 3b disease were comparable to those of healthy controls. Neither the CAR nor the DCD showed stepwise changes as the disease stage worsened. When patients were subgrouped according to their Eastern Cooperative Oncology Group (ECOG) PS score, there was stepwise reduction in the CAR and flattening of the DCD as the PS score increased. Both an abolished CAR and a flattened DCD were common in patients with ECOG PS scores of 3 and 4. These results indicate that alteration of the diurnal cortisol rhythm in patients with advanced LC is more closely associated with their PS score than with their clinical disease stage. Gradual alteration of the CAR and DCD, indicative of loss of 24-h cortisol rhythm, in concert with increase in PS score implies that endogenous circadian rhythms may also be disintegrating as the PS score worsens in these patients. (Author correspondence: ryunsup@yahoo.co.kr ).     

The role of cortisol in the peripheral granulocyte response to insulin-induced hypoglycaemia in man

Peripheral blood leukocyte counts and plasma hormonal changes in response to acute insulin-induced hypoglycaemia were examined in 16 patients undergoing assessment of pituitary function. Eight subjects had a normal cortisol secretory response (Group 1), and 8 patients had definite hypopituitarism in whom the cortisol responses were deficient or absent (Group 2). An equivalent degree of hypoglycaemia was achieved in both groups. In Group 1a biphasic rise in leukocyte count occurred following hypoglycaemia, with an early rise in lymphocytes at 15 minutes after the acute hypoglycaemic reaction, and a later rise in granulocytes. A similar rise in lymphocytes was observed in Group 2, but the rise in the granulocyte count was attenuated, increasing from a basal value of 3.6 +/- 0.6 x 10(9) cells/L to a peak of 7.4 +/- 1.1 x 10(9) cells/L, compared with a peak of 11.7 +/- 1.2 x 10(9) cells/L in Group 1 (P less than 0.05). The usual increment in plasma cortisol in response to hypoglycaemia occurred in Group 1, but plasma cortisol did not rise in Group 2. A correlation was observed between the magnitude of the granulocyte rise and the increment in plasma cortisol in individual subjects (r = 0.64, P less than 0.02). This suggests that the rise in peripheral granulocytes following insulin-induced hypoglycaemia in man is mediated by cortisol released from the adrenal gland, following activation of the hypothalamic-pituitary-adrenal axis.