The cortisol awakening response and autonomic nervous system activity during nocturnal and early morning periods

The current study focuses on autonomic nervous system activity during sleep as a physiological aspect of sleep quality, and investigated the associations between the cortisol awakening response (CAR) and autonomic activity during sleep and after awakening. Ambulatory electrocardiograms were obtained from 20 participants, who also provided saliva samples (at the time of awakening, and 30, 45, and 60 min after awakening) and rated the subjective quality of their sleep at home. Autonomic activity was assessed with the Lorenz plot indices, cardiac sympathetic index (CSI) and cardiac vagal index. Total salivary cortisol secretion after awakening was calculated as area under the curve with respect to ground (AUC(G)) and increase (AUC(I)). After controlling for confounding factors, including sleep duration and awakening time, cortisol AUC(G) and AUC(I) were both found to be negatively correlated with CSI during the 30 min before and after awakening: before (r = -0.526 and -0.601 respectively) and after (r = -0.540 and -0.493 respectively). Self-reported sleep quality was not associated with the CAR. These results suggest that the CAR is negatively affected by basal sympathetic activity immediately before and after awakening, but not affected by subjective sleep quality. Physiological arousals around the time of awakening might inhibit the CAR.     

The awakening cortisol response: no evidence for an influence of body posture

It has recently been reported that the orthostatic challenge associated with postural change from sitting to an upright position is stimulatory to the hypothalamic-pituitary-adrenal axis as evidenced by increased salivary free cortisol. This stimulatory influence is potentially a confound for the many psychoneuroendocrine studies for which salivary free cortisol is the main dependent variable. This particularly relates to laboratory psychosocial stress procedures in which subjects are invited to stand in order to deliver public speech and the studies which have explored the cortisol response to awakening in which postural shift has not been controlled for. We therefore examined, in a balanced cross over design whether the awakening cortisol response was influenced by standing, shortly after awakening or remaining supine during the response study period. In addition and in the same subjects we measured the cardiovascular response and saliva cortisol response to the orthostatic challenge of shifting from a supine to a standing position later in the diurnal cortisol cycle. The expected cortisol response to awakening was demonstrated but there was no evidence that the postural shift, supine to standing, confounded the response. This same postural shift later in the day induced the expected increase in heart rate but cortisol simply followed the circadian decline. Under the conditions of the present study we found no evidence that the postural shift supine to standing could induce a cortisol secretory episode such as to contribute towards the awakening response.     

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.     

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.     

The awakening cortisol response and blood glucose levels

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.     

Effects of nighttime low frequency noise on the cortisol response to awakening and subjective sleep quality

The effects of night-time exposure to traffic noise (TN) or low frequency noise (LFN) on the cortisol awakening response and subjective sleep quality were determined. Twelve male subjects slept for five consecutive nights in a noise-sleep laboratory. After one night of acclimatisation and one reference night, subjects were exposed to either TN (35dB L(Aeq), 50dB L(Amax)) or LFN (40dB L(Aeq)) on alternating nights (with an additional reference night in between). Salivary free cortisol concentration was determined in saliva samples taken immediately at awakening and at three 15-minute intervals after awakening. The subjects completed questionnaires on mood and sleep quality. The awakening cortisol response on the reference nights showed a normal cortisol pattern. A significant interaction between night time exposure and time was found for the cortisol response upon awakening. The awakening cortisol response following exposure to LFN was attenuated at 30 minutes after awakening. Subjects took longer to fall asleep during exposure to LFN. Exposure to TN induced greater irritation. Cortisol levels at 30 minutes after awakening were related to "activity" and "pleasantness" in the morning after exposure to LFN. Cortisol levels 30 minutes after awakening were related to sleep quality after exposure to TN. This study thus showed that night time exposure to LFN may affect the cortisol response upon wake up and that lower cortisol levels after awakening were associated with subjective reports of lower sleep quality and mood.     

Self-reported symptoms of depressed mood, trait anxiety and aggressive behavior in post-pubertal adolescents: Associations with diurnal cortisol profiles

The association between self-reported symptoms and diurnal cortisol profiles was studied in post-puberty adolescents (29 boys and 29 girls, M_age = 15.06 years). The adolescents completed the Children's Depression Inventory, State Trait Anxiety Inventory, and an Aggressive behavior scale. The diurnal cortisol profile was derived from three saliva samples, collected at awakening, noon and evening on a week-end day. Univariate repeated measurement regressions revealed that depressed mood and trait anxiety were strongly and aggressive behavior was weakly related to the diurnal cortisol profile: greater emotional distress was associated with flatter diurnal cortisol profiles. Multivariate analysis, however, revealed that only trait anxiety made an independent contribution. Further analyses suggested that trait anxiety was related to elevated evening cortisol rather than to decreased awakening cortisol and that from a trait anxiety score of 38 onwards, high anxious adolescents show clearly higher evening cortisol than low anxious adolescents. These data suggest that anxiety disorder co-morbidity might explain some of the differences in HPA-axis function among depressed patients.     

Salivary cortisol for monitoring adrenal activity during marathon runs

In non-elite male runners (n = 8), changes in adrenal activity were monitored by measurement of salivary cortisol in samples collected at 4-mile intervals during marathon runs. These changes were compared with those in similarly timed samples collected on rest days. Immediately prior to the Cardiff marathon, at 09.00 h, mean salivary cortisol concentrations (21.5 nmol/l) were higher than those in similarly timed rest day samples (14.9 nmol/l). Cortisol concentrations increased during the marathon, and although values at 25 miles were high (79.4 nmol/l), maximum values (87.9 nmol/l) were observed in samples collected 30 min after completion of the run. Some Cardiff marathon runners also participated in the Bristol marathon (n = 4) and a non-competitive event (n = 3). The changing pattern in secretory activity was similar in all events. The easy collection of saliva without cessation of exercise is ideal for monitoring the hormonal response to exercise.     

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.     

High correlation between salivary cortisol awakening response and the psychometric profiles of healthy children

Background

Cortisol awakening response (CAR) as an indicator of psychological stress and related physical and psychiatric diseases has attracted growing attention from researchers. Although CAR changes have been investigated extensively in children with behavioral and psychiatric disorders, the association between CAR and conventional psychometric scales for healthy children has not been reported. The aim of this study was to investigate the association between salivary CAR and subscales of Profiles of Mood States (POMS), a self-assessment questionnaire widely used to evaluate the temporal emotional states of healthy children.

Findings

This study included 18 healthy girls aged 13–16 years. Saliva was collected immediately on awakening, 30 min and 60 min after waking, and then at 2-hour intervals from 9 am to 5 pm. The current mood state, including depression, anxiety, fatigue, and other psychometric profiles were assessed using POMS. The magnitude of salivary CAR and the area under the concentration-time curve (AUC) for diurnal salivary cortisol were compared with the profiles. There were significant positive correlations between the magnitude of CAR and the POMS subscales for "Depression-Dejection", "Tension-Anxiety", "Fatigue", and "Confusion". No correlation was found between the AUC salivary cortisol level and the psychometric profiles.

Conclusions

Salivary CAR was associated with various mood states of healthy female children but diurnal salivary cortisol AUC was not. Salivary CAR may be a biomarker of the physical and mental condition of healthy female children.

     

Negative emotionality, depressive symptoms and cortisol diurnal rhythms: analysis of a community sample of middle-aged males

Prior research suggests that individuals with particular personality traits, like negative emotionality, are at greater risk for adverse health outcomes. Despite bivariate associations between negative emotionality, depressive symptoms and the hypothalamic pituitary adrenal axis (HPA axis), few studies have sought to understand the biological pathways through which negative emotionality, depressive symptomatology and cortisol—one of the primary hormonal products of the HPA axis—are associated. The present study explored whether negative emotionality influenced cortisol dysregulation through current depressive symptomatology and whether negative emotionality served as a moderator of the relationship between depressive symptoms and cortisol. In the community-based Vietnam Era Twin Study of Aging, 783 male twins completed two days of cortisol saliva sampling in their natural environments. Three measures of cortisol were analyzed: waking levels, the cortisol awakening response, and the peak to bed slope. Depressive symptoms significantly mediated the associations between negative emotionality and the peak to bed slope. A 2-way interaction between depressive symptoms and negative emotionality was significant for the peak to bed slope and for waking levels of cortisol. Exploration of the interactions illustrated that depressive symptoms only affected cortisol slopes at average or high levels of negative emotionality and only affected waking levels at low levels of negative emotionality. Negative emotionality and depressive symptoms were not related to the cortisol awakening response. This is the first study to find indirect associations between negative emotionality and peak to bed cortisol slopes through depressive symptoms. These findings illustrate the complex interplay between personality characteristics, depressive symptoms and different indices of the cortisol diurnal rhythm.     

Relationship between 24-hour urinary-free cortisol excretion and salivary cortisol levels sampled from awakening to bedtime in healthy subjects

The utility of repeated salivary cortisol sampling as a substitute for 24-hour urinary-free cortisol (UFC) assessment was examined. Forty-four participants completed both 24-hour collections and 6 salivary collections at wake-up, 08:00, 12:00, 16:00, 20:00 and bedtime, during the same 24-hour period. The results demonstrated that mean, maximum, and amplitude (maximum minus minimum) for salivary cortisol all correlated positively with urinary cortisol, but the associations of these variables with urinary-free cortisol excretion were relatively small. Furthermore, a single salivary sample taken at wake-up was as good an indicator of overall cortisol production as the measures derived from multiple salivary samples. An examination of subject compliance indicated that many subjects failed to collect the timed salivary collections as instructed. The authors conclude that diurnal salivary cortisol sampling versus 24-hour urinary cortisol collections are likely to provide different information about ambient hypothalamic-pituitary-adrenal productivity, and therefore these measures should not be used interchangeably. In addition, subject compliance is a serious consideration in designing studies that employ home salivary collections.     

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 ).     

Shift work parameters and disruption of diurnal cortisol production in female hospital employees

Shift work is associated with an increased risk of cardiovascular diseases (CVD). Disruption of cortisol production is a potential underlying mechanism. This study explored the associations of diurnal quantity and pattern of cortisol production in relation to (1) current shift work status (exclusive day versus rotating days and nights), (2) years of past shift work and (3) parameters of rotating shift work (timing, length and intensity). Female hospital employees (160 day workers and 168 rotating shift workers) from southeastern Ontario, Canada, participated in a cross-sectional study. Participants completed a baseline questionnaire and measures of body height, weight, and waist circumference were taken. Midstream urine samples were collected over two separate 24-hour periods to measure creatinine-adjusted cortisol. Total diurnal cortisol production and pattern were described with two measures of the area under the curve. The effect of shift work on cortisol was modeled using multivariable linear regression analyses. Cortisol production in day workers and shift workers on their day shift were similar; however, shift workers on the night shift had flatter diurnal cortisol curves and produced less cortisol. This suggests that night work is associated with an acute attenuation of cortisol production.     

Changes in salivary cortisol concentrations during a 24-hour period in dogs.

The purpose of this investigation was to clarify whether salivary cortisol secretion in dogs had a circadian rhythm. Saliva sampling during a 24-hour period was performed in 4 non-consecutive days. Eight adult beagle dogs (4 males and 4 females) were divided into 4 groups, and 2 dogs (1 male and 1 female) were used for each repetition. Saliva samples were taken at 1 h intervals from 9:00 a. m. to 9:00 a. m. of the following day. Salivary cortisol concentrations were determined using enzyme-linked immunosorbent assay. No circadian rhythm was detected for salivary cortisol, and the differences among salivary cortisol concentrations measured every hour were not demonstrated during a 24-hour period in dogs.     

Salivary concentration of progesterone and cortisol significantly differs across individuals after correcting for blood hormone values

Between‐individual variation of salivary progesterone (P4) and cortisol levels does not always closely reflect blood hormone concentrations. This may be partly a function of individual differences in salivary hormone excretion. We tested whether time of day at sampling and ethnicity contributed to individual variation in salivary hormones after adjusting for blood hormone levels. Forty‐three Caucasian and 15 Japanese women (18–34 years) collected four sets of matched dried blood spot (DBS) and saliva specimens across a menstrual cycle (N = 232 specimen sets). Linear fixed‐effects (LFE) models were used to estimate the effects of diurnal variation and ethnicity on salivary P4 and cortisol while adjusting for DBS levels. For each hormone, women with exclusively positive or negative residuals (unexplained variance) from the LFE models were categorized as high‐ or low‐saliva‐to‐DBS hormone ratio (SDR; high or low salivary secretors), respectively. We found that salivary P4 (P < 0.05) was significantly higher in early morning compared to the afternoon, after controlling for DBS levels, ethnicity, and BMI. After further adjusting for this diurnal effect, significant individual variation in salivary P4 and cortisol remained: sixteen and nine women, respectively were categorized as low or high salivary secretors for both hormones (P < 0.001), suggesting systematic individual‐specific variation of salivary hormonal concentration. We conclude that when saliva is used to quantify P4 or cortisol levels, time of day at sampling should be controlled. Even with this adjustment, salivary P4 and cortisol do not closely mirror between‐ individual variation of serum P4 and cortisol in a substantial proportion of individuals. Am J Phys Anthropol 149:231–241, 2012. © 2012 Wiley Periodicals, Inc.     

Electronic monitoring of salivary cortisol sampling compliance in daily life

Naturalistic research methods have been developed to collect data in the daily environment, providing ecological valid measures. Recent reports suggest, however, that compliance with fixed time sampling protocols may be problematic and can bias results. This study investigated compliance with an intensive, random time sampling protocol for salivary cortisol and effects of non-compliance on cortisol results. Twenty female twin pairs and nineteen of their sisters were instructed to take saliva samples when signaled at ten unpredictable moments on each of five consecutive days. Subjects recorded collection times, unaware that compliance with the sampling protocol was being investigated by means of electronic monitoring devices. Samples taken < or = 15 min after the signal, according to self-report, were defined as adherent to the protocol. Samples taken < or = 10 min after the self-reported collection time, according to the monitor, were defined as accurate. Self-reported adherence to the sampling protocol was 96.4%. Verified compliance was somewhat lower, with 81% of all saliva samples accurately timed. Contrary to previous reports, inclusion of non-compliant samples in the analysis did not distort the cortisol diurnal profile. Intensive, random time sampling appears to have advantages over fixed time sampling for obtaining valid cortisol profiles when researchers do not have devices to monitor compliance. Results indirectly support the validity of momentary self-report data about daily experiences obtained with the same sampling methods.     

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. (Author correspondence: burch@mailbox.sc.edu)     

Perceived discrimination and diurnal cortisol: examining relations among Mexican American adolescents

Perceived discrimination remains a salient and significant environmental stressor for ethnic and racial minority youth. Although many studies have examined the impact of racial/ethnic discrimination on mental health symptomatology and physical health, little is known of the potential physiological processes underlying such experiences, especially during adolescence. In an attempt to understand how varying perceptions of discrimination relate to functioning of the hypothalamic-pituitary-adrenal axis (HPA axis), the current study examined the relation between Mexican American adolescents' (N = 100, M(age) = 15.3 years old) perceptions of discrimination and aspects of their diurnal cortisol profiles. Three salivary samples (wakeup, +30 waking, bedtime) were collected across 3 days (total of 9 samples). Utilizing multi-level modeling, results revealed that adolescents' perceived discrimination related to greater overall cortisol output (area under the curve; AUC) after controlling for other life stressors, depressive symptoms, family income, acculturation level, daily stress levels and daily behaviors. Findings also revealed that perceived discrimination was marginally related to a steeper cortisol awakening response (CAR). Together, these findings suggest that perceived discrimination is a salient and impactful stressor for Mexican American adolescents. Understanding the physiological correlates of discrimination can provide insight into larger health disparities among ethnic and racial minority individuals.     

Saliva and serum cortisol dynamics following intravenous dexamethasone in normal volunteers

In order to further explore the utility of saliva cortisol as an accurate measure of adrenal steroid production, dexamethasone (DEX) and saline were administered intravenously at 0800h to eight normal male volunteers in a randomized design, and the effects on serum and saliva cortisol concentrations were measured at hourly intervals from 0800h-2300h. Saliva cortisol values were highly correlated to serum cortisol levels within-subjects under both conditions (r = 0.78, p less than 0.025), however correlations were reduced in the DEX day sample pairs. Across-subject correlations at each time point were considerably more variable, reflecting interindividual differences in the saliva to serum cortisol ratios. No consistent time lag of saliva cortisol values in response to serum cortisol fluctuations was observed. These data suggest that saliva cortisol is an excellent index of changes in adrenal production of cortisol over time within individuals; however, it also suggests that salivary cortisol measures have less usefulness in comparing values across groups of individuals.