Circadian Rhythm of Salivary Cortisol in Asian Elephants (Elephas maximus): A Factor to Consider During Welfare Assessment

Elevated glucocorticoid levels during an extended time period might be a stress indicator in nonhuman animals. Therefore, knowledge of the circadian pattern of cortisol secretion is very important to correctly interpret data obtained for welfare assessment of animals in captivity through salivary cortisol. In order to define the circadian rhythm of salivary cortisol secretion in the Asian elephant (Elephas maximus), morning and evening saliva samples of 3 Asian elephants were collected and analyzed by radioimmunoassay. Significantly higher salivary cortisol concentrations were found in the morning than in the evening in all individuals. These results show that salivary cortisol of Asian elephants follows a diurnal pattern of secretion, which could be taken into account when using this methodology to assess welfare in captive Asian elephants.     

Diurnal variation in glucose tolerance in rats after experimental changes in glucocorticoid rhythm

Control rats manifested an unmarked circadian rhythm in blood sugar during evening hours. The morning-evening difference in blood sugar increased after adrenalectomy, disappeared after weekly substitution therapy with cortisol and was inverted after evening injections of cortisol to rats with intact adrenals. Evening injections of the hormone were also more efficacious from the standpoint of glucose tolerance modulation.     

Development of Salivary Cortisol Circadian Rhythm and Reference Intervals in Full-Term Infants

BackgroundCortisol concentrations in plasma display a circadian rhythm in adults and children older than one year. Earlier studies report divergent results regarding when cortisol circadian rhythm is established. The present study aims to investigate at what age infants develop a circadian rhythm, as well as the possible influences of behavioral regularity and daily life trauma on when the rhythm is established. Furthermore, we determine age-related reference intervals for cortisol concentrations in saliva during the first year of life.Methods130 healthy full-term infants were included in a prospective, longitudinal study with saliva sampling on two consecutive days, in the morning (07:30-09:30), noon (10:00-12:00) and evening (19:30-21:30), each month from birth until the infant was twelve months old. Information about development of behavioral regularity and potential exposure to trauma was obtained from the parents through the Baby Behavior Questionnaire and the Life Incidence of Traumatic Events checklist.ResultsA significant group-level circadian rhythm of salivary cortisol secretion was established at one month, and remained throughout the first year of life, although there was considerable individual variability. No correlation was found between development of cortisol circadian rhythm and the results from either the Baby Behavior Questionnaire or the Life Incidence of Traumatic Events checklist. The study presents salivary cortisol reference intervals for infants during the first twelve months of life.ConclusionsCortisol circadian rhythm in infants is already established by one month of age, earlier than previous studies have shown. The current study also provides first year age-related reference intervals for salivary cortisol levels in healthy, full-term infants.     

Do plasma ACTH and cortisol concentrations in the late-gestation fetal sheep vary diurnally?

This study tested the hypothesis that fetal plasma ACTH and cortisol concentrations vary diurnally, and the mean concentration and the amplitude of the rhythm vary as a function of fetal gestational age. Nine chronically-catheterized fetal sheep were studied between 120 and 142 days' gestation. All of the fetuses were born spontaneously and alive. The pregnant ewes were maintained in a room with a regular light cycle (on at 07.30, off at 17.30). Food and water were available ad libitum. Blood samples were drawn at 4-h intervals throughout a 24-h period. There were no significant daily variations in fetal plasma ACTH, cortisol, or progesterone concentrations, except in the last 3 days of fetal life. In these fetuses ACTH and cortisol concentrations were increased in the afternoon and evening. We conclude that there is no diurnal rhythm in ovine fetal hypothalamo-pituitary-adrenal axis activity, and that the increased plasma concentrations of ACTH and cortisol in the afternoon and evening hours of the last few days of fetal life might be a response to increased uterine contraction activity.     

Abnormality of circadian rhythm of serum melatonin and other biochemical parameters in fibromyalgia syndrome

Fibromyalgia syndrome (FMS) is a complex chronic condition causing widespread pain and variety of other symptoms. It produces pain in the soft tissues located around joints throughout the body. FMS has unknown etiology and its pathophysiology is not fully understood. However, abnormality in circadian rhythm of hormonal profiles and cytokines has been observed in this disorder. Moreover, there are reports of deficiency of serotonin, melatonin, cortisol and cytokines in FMS patients, which are fully regulated by circadian rhythm. Melatonin, the primary hormone of the pineal gland regulates the body's circadian rhythm and normally its levels begin to rise in the mid-to-late evening, remain high for most of the night, and then decrease in the early morning. FMS patients have lower melatonin secretion during the hours of darkness than the healthy subjects. This may contribute to impaired sleep at night, fatigue during the day and changed pain perception. Studies have shown blunting of normal diurnal cortisol rhythm, with elevated evening serum cortisol level in patients with FMS. Thus, due to perturbed level of cortisol secretion several symptoms of FMS may occur. Moreover, disturbed cytokine levels have also been reported in FMS patients. Therefore, circadian rhythm can be an important factor in the pathophysiology, diagnosis and treatment of FMS. This article explores the circadian pattern of abnormalities in FMS patients, as this may help in better understanding the role of variation in symptoms of FMS and its possible relationship with circadian variations of melatonin, cortisol, cytokines and serotonin levels.     

Circadian rhythm of hypothalamo-hypophyseal-adrenal activity in the chicken.

Corticosteroid production, ACTH content in the adenohypophysis and CRF content in the median eminence were studied in vitro and in vivo in the 3-weeks-old chicken according to SAFFRAN and SCHALLY in four different parts of the day: at 6 and 12 a.m., and 6 and 12 p.m. The chicken adrenals in vitro produced only corticosterone in fluorimetrically measurable amounts, with the maximum during the day and the minimum in the evening and at night. Sensitivity to ACTH of the adrenals in vitro was higher during the day than in the evening or at night. After paper-chromatographic separation, steroid hormones equivalent to corticosterone and cortisol could be detected fluorimetrically in the plasma. The "cortisol" level was about 2-2.5 times higher than the corticosterone level. Plasma "cortisol" level displayed the peak at 6 a.m. and the minimum at 12 p.m., while corticosterone at 12 a.m. and 12 p.m., respectively. ACTH content in the adenohypophysis was lowest at 6 a.m. then increased gradually until 12 p.m. CRF level in the median eminence fell during the forenoon, was lowest at noon, to rise up to 6 p.m. and persist at a high level between 6 p.m. and 6 a.m. Thus, in the 3-week-old chicken the functioning of the hypothalamo-hypophyseal-adrenal system displays a circadian rhythm characteristic of animals showing diurnal activity.     

Lack of adult-type salivary cortisol circadian rhythm in hospitalized preterm infants

BACKGROUND/AIMS: Knowledge of the presence or absence of cortisol (F) circadian rhythm in preterm infants is important for the interpretation of F measurements made in samples taken for both clinical and research purposes. Little is known about its emergence in very preterm infants. This study examines circadian rhythm in F secretion in hospitalized infants born before 30 weeks' gestation. METHODS: Design: Prospective longitudinal observational study. Subjects: 11 infants admitted consecutively and born before 30 completed weeks of gestation. Measurements: F was measured by highly specific radioimmunoassay on morning and evening saliva samples gathered at weekly intervals until discharged home. Circadian rhythm was defined as > or =40% reduction from morning to evening level. RESULTS: For all data, the median salivary F was 10.3 nmol/l (range <0.5-372.8). F levels were highest in the first 3 weeks of life. No infants displayed classical circadian rhythm for 4 weeks or more prior to being discharged from hospital. The other infants showed randomly distributed morning and evening F values with a trend in 4 infants towards periods of consistently higher evening than morning values. CONCLUSION: Adult-type F circadian rhythm is rarely evident in hospitalized preterm infants born before 30 weeks' gestation.     

Role of photoperiodicity and circadian rhythm of glucocorticoids in synchronizing the fluctuations in free-radical oxidation of lipids in rats

A biphasic circadian rhythm in the content of liver lipid peroxidation products has been demonstrated in male Wistar rats housed under the conditions of 12L: 12D, with 3 hours of morning and evening twilight. Maxima of the concentration of the products were observed in the morning and early at night. The rhythm of lipid anti-oxidative activity was found in an anti-phase. Inversion of both the L: D cycle and glucocorticoid circadian rhythms (cortisol injections) led after 14-16 days to the same shifts in the rhythm of anti-oxidative activity. The data indicate that glucocorticoids modulate the diurnal rhythms of lipid anti-oxidative activity and may be responsible for the shifts in the rhythms of free radical oxidation, induced by inversion of the L: D cycle.     

Genetic and environmental influences on individual differences in cortisol level and circadian rhythm in middle childhood

Individuals differ widely in cortisol output over the day, but the etiology of these individual differences remains poorly understood. Twin studies are useful for quantifying genetic and environmental influences on the variation in cortisol output, lending insight into underlying influences on the components of Hypothalamic-Pituitary-Adrenal (HPA) axis functioning. Salivary cortisol was assayed on 446 twin pairs (157 monozygotic, 289 dizygotic; ages 7-8). Parents helped youth collect saliva 30 min after waking, mid-afternoon, and 30 min prior to bedtime across 3 consecutive days. We used hierarchical linear modeling to extract predicted cortisol levels and to distinguish cortisol's diurnal rhythm using a slopes-as-outcome piecewise growth curve model; two slopes captured the morning-to-afternoon and afternoon-to-evening rhythm, respectively. Separate genetic models were then fit to cortisol level at waking, mid-afternoon, and evening as well as the diurnal rhythm across morning-to-afternoon and afternoon-to-evening hours. Three results from these analyses are striking. First, morning-to-afternoon cortisol level showed the highest additive genetic variance (heritability), consistent with prior research. Second, cortisol's diurnal rhythm had an additive genetic component, particularly across the morning-to-afternoon hours. In contrast, additive genetic variation did not significantly contribute to variation in afternoon-to-evening slope. Third, the majority of variance in cortisol concentration was associated with shared family environments. In summary, both genetic and environmental factors influence cortisol's circadian rhythm, and they do so differentially across the day.     

Parametric and nonparametric entrainment of circadian locomotor rhythm in the Japanese honeybee Apis cerana japonica

The circadian rhythm of locomotor activity in the Japanese honeybee Apis cerana japonica was studied to determine the involvement of parametric and/or nonparametric entrainment. The rhythm was entrained to a skeleton photoperiod in which a 1-h first light pulse was imposed in the morning along with a second light pulse in the evening, as well as to a complete photoperiodic regime (LD 12:12). However, the timing of peak activity relative to the lights-off in the evening in the skeleton photoperiod was earlier than that in the complete photoperiod. A single daily light pulse in the evening entrained the rhythm, whereas a daily light pulse in the morning allowed free-running as in constant darkness. The free-running period (τ) of locomotor activity in constant light became longer as the light intensity increased. A Winfree's type I phase response curve of the locomotor activity rhythm was obtained using a single 1-h light pulse. The results suggest that both parametric and nonparametric entrainment are involved in the circadian rhythm of individual locomotor activity in this honeybee.     

Opiate receptor blockade and diurnal pituitary and adrenal hormone levels

Peripheral pituitary hormone levels exhibit circadian variations though the mechanism of these changes is unknown. In order to investigate the possible role of endogenous opiates in such changes we have studied the influence of opiate receptor blockade with naloxone (6.8 mg) on pituitary hormones in the morning and again in the evening in six normal male volunteers. Basal ACTH, cortisol, aldosterone and prolactin were higher in the morning than in the evening. Following naloxone at 0700h both ACTH and cortisol rose indicating a tonic inhibition of ACTH by endogenous opiates at that time. At 2230h cortisol rose following naloxone but ACTH did not, suggesting that endogenous opiates do not play an important role in the diurnal rhythm of this hormone and consistent with the suggestion that endogenous opiates can effect cortisol levels independently of their action on ACTH. Neither aldosterone nor prolactin were influenced by naloxone. In contrast TSH was unaffected by naloxone in the morning but fell in the evening (mean + SE decrement over 120 min -0.6 +/- 0.3 mU/l as compared with the control +0.6 +/- 0.4 mU/l; p less than 0.01). Thus, endogenous opiates probably tonically stimulates TSH levels in the evening when TSH may increase and possibly play a role in the circadian rhythm of TSH.     

Relative Metabolic Stability,but Disrupted Circadian Cortisol Secretion during the Fasting Month of Ramadan

Background

Chronic feeding and sleep schedule disturbances are stressors that exert damaging effects on the organism. Practicing Muslims in Saudi Arabia go through strict Ramadan fasting from dawn till sunset for one month yearly. Modern era Ramadan practices in Saudi Arabia are associated with disturbed feeding and sleep patterns, namely abstaining from food and water and increasing daytime sleep, and staying awake and receiving food and water till dawn.

Hypothesis

Strict Ramadan practices in Saudi Arabia may influence metabolism, sleep and circadian cortisol secretion.

Protocol

Young, male Ramadan practitioners were evaluated before and two weeks into the Ramadan. Blood samples were collected at 9.00 am and 9.00 pm for measurements of metabolic parameters and cortisol. Saliva was collected serially during the day for cortisol determinations.

Results

Ramadan practitioners had relative metabolic stability or changes expected by the pattern of feeding. However, the cortisol circadian rhythm was abolished and circulating insulin levels and HOMA index were increased during this period.

Discussion

The flattening of the cortisol rhythm is typical of conditions associated with chronic stress or endogenous hypercortisolism and associated with insulin resistance.

Conclusions

Modern Ramadan practices in Saudi Arabia are associated with evening hypercortisolism and increased insulin resistance. These changes might contribute to the high prevalence of chronic stress-related conditions, such as central obesity, hypertension, metabolic syndrome and diabetes mellitus type 2, and their cardiovascular sequelae observed in the Kingdom.     

Entrainment of the circadian rhythm in the rat pineal N-acetyltransferase activity by prolonged periods of light

Summary Entrainment of the circadian rhythm in the pineal N-acetyltranferase activity by prolonged periods of light was studied in rats synchronized with a light:dark regime of 1212 h by observing phase-shifts in rhythm after delays in switching off the light in the evening or after bringing forward of the morning onset of light. When rats were subjected to delays in switching off the light of up to 10 h and then were released into darkness, phase-delays of the evening N-acetyltransferase rise during the same night corresponded roughly to delays in the light switch off. However, phasedelays of the morning decline were much smaller. After a delay in the evening switch off of 11 h, no N-acetyltransferase rhythm was found in the subsequent darkness. The evening N-acetyltransferase rise was phase-delayed by 6.2 h at most 1 day after delays. Phase-delays of the morning Nacetyltransferase decline were shorter than phasedelays of the N-acetyltransferase rise by only 0.7 h to 0.9 h at most. Hence, 1 day after delays in the evening switch off, the period of the high night N-acetyltransferase activity may be shortened only slightly. The N-acetyltransferase rhythm was abolished only after a 12 h delay in switching off the light.Rats were subjected to a bringing forward of the morning light onset and then were released into darkness 4 h before the usual switch off of light. In the following night, the morning N-acetyltransferase decline, but not the evening rise, was phase advanced considerably. Moreover, when the onset of light was brought forward to before midnight, the N-acetyltransferase rise was even phase-delayed. Hence, 1 day after bringing forward the morning onset of light, the period of the high night N-acetyltransferase activity may be drastically reduced. When rats were subjected to a 4 h light pulse around midnight and then released into darkness, the N-acetyltransferase rhythm in the next night was abolished.The data are discussed in terms of a two-component pacemaker controlling the N-acetyltransferase rhythm. It is suggested that delays in the evening switch off of light may disturb the N-acetyltransferase rhythm the next day only a little, as the morning component may adjust to phasedelays of the evening component almost within one cycle. On the other hand, bringing forward the morning onset of light may disturb the N-acetyltransferase rhythm heavily the next day, as the evening component not only does not adjust to phase-advances of the morning component, but it may even be phase-delayed when the light onset occurs before midnight.Abbreviations NAT N-acetyltransferase - PRC phase response curve - E evening component of the N-acetyltransferase rhythm or of its pacemaker - M morning component of the N-acetyltransferase rhythm or of its pacemaker - LD xy light dark cycle comprising x h of light and y h of darkness     

Circadian rhythmicity of cortisol and body temperature: morningness-eveningness effects

The purpose of this study was to describe and compare the circadian rhythm of body temperature and cortisol, as well as self-reported clock times of sleep onset and offset on weekdays and weekends in 19 healthy adult "larks" (morning chronotypes) and "owls" (evening chronotypes), defined by the Home and Ostberg questionnaire. Day-active subjects entered the General Clinical Research Center, where blood was sampled every 2 h over 38 h for later analysis for cortisol concentration by enzyme immunoassay. Rectal body temperature was measured continuously. Lights were turned off at 22:30 for sleep and turned on at 06:00, when subjects were awakened. The acrophases (peak times) of the cortisol and temperature rhythms occurred 55 minutes (P < or = .05) and 68 minutes (P < .01), respectively, earlier in the morningness group. The amplitude of the cortisol rhythm was lower in the eveningness than in the morningness group (P = n.s.). Subject groups differed on all indices of habitual and preferred timing of sleep and work weekdays and weekends (P = .05-.001).     

Beyond physiological hypoarousal: The role of life stress and callous-unemotional traits in incarcerated adolescent males

The development of antisocial behavior in youth has been examined with neurobiological theories that suggest that adolescents who are less responsive to their environments are less likely to develop empathy in the absence of extant physiological arousal. However, little attention is paid to these individuals' social context. Individuals with adverse early experiences can also exhibit attenuated physiological arousal. The current investigation examines whether psychopathic symptoms or life stress exposure is associated with cortisol and its diurnal rhythm within 50 incarcerated adolescent boys (14–18 years old). Ten saliva cortisol samples were collected 1–2 weeks after admission to a maximum-security juvenile facility. Hierarchical Linear Modeling distinguished waking cortisol levels, the awakening response (CAR) and the diurnal rhythm. Multiple interviews and self-report measures of CU traits and stressor exposure were collected. Boys with higher levels of CU traits or greater life stress exposure had flat diurnal rhythms and a steeper awakening response in analyses with lifetime stress exposure specifically. Nonetheless, boys who were elevated on both CU traits and prior stress exposure had steeper diurnal rhythms. These results extend neurobiological theories of cortisol and illustrate that boys with the combination of severe stress with CU traits have a unique physiological profile.     

Diurnal rhythm in the counts and types of milk somatic cells,neutrophil phagocytosis and plasma cortisol levels in Karan Fries cows during different seasons and parity

Chances of mammary infections are comparatively higher in high producing cows during harsh environmental conditions and are usually characterised by changes occurring in various somatic cells secreted in the milk and their activities. The present study was conducted to record diurnal rhythmicity in milk somatic cell counts (SCC), neutrophil: macrophage (N: M) ratio, phagocytic activity (PA) of milk neutrophils and plasma cortisol concentrations during different seasons and parity in high producing Karan Fries cows. Values of milk SCC, N: M ratio and plasma cortisol levels were lowest during thermoneutral (TN), intermediate in winter and highest during the summer season. Diurnal rhythm in the milk SCC and N: M ratio was noticed in the summer while plasma cortisol exhibited diurnal rhythm in both winter and summer seasons. Milk SCC, N: M ratio and plasma cortisol increased in multiparous cows, but diurnal variation was noticed only in the N: M ratio and plasma cortisol in cows having more than four parity. Phagocytic activity of milk neutrophils was highest during TN, intermediate in winter and lowest during the summer season. Phagocytic activity was higher and similar in cows up to fourth parity but decreased in subsequent lactation cycles. Diurnal rhythm in the PA was noticed in winter and summer seasons and in cows having more than four parity where morning samples showed higher phagocytosis as compared to the evening samples. These results can be used for immunomodulatory interventions and therapeutic approaches in treating mastitis of crossbred cows reared under tropical conditions.     

Environmental enrichment in early life affects cortisol patterns in growing pigs

Effects of environmental enrichment at different stages of life on stress physiology of pigs were investigated in a trial with 63 groups, each of four siblings. In each of the three growing phases (suckling 0 to 4 weeks of age, nursery 5 to 9 weeks, fattening 10 to 24 weeks) pens either were (=E) or were not (=0) enriched. Accordingly, the treatments were (i) 000, (ii) E00, (iii) EE0, (iv) 00E, (v) 0EE and (vi) EEE. The enrichment material, renewed twice daily to leave a thin layer, consisted of wood shavings and chopped straw. Salivary cortisol was sampled hourly from 0700 to 1900 h at the age of 9 and 21 weeks. The presence of a circadian secretion rhythm was evaluated by an intra-assay coefficient of variation-based method. An adrenocorticotropic hormone test was performed at 21 weeks. Treatment effects on the odds of a physiological cortisol rhythm were assessed by logistic regression, and effects on cortisol concentrations with a repeated measures GLM. Substrate-enrichment from 0 to 9 weeks of age increased the odds of a rhythm as compared to barren housing (odds ratio (OR) = 30.0, P < 0.01). A flat cortisol secretion pattern may indicate chronic stress and/or delayed maturation of the rhythm. Barren as compared to enriched rearing (0 to 4 weeks of age) seemed to cause a blunted secretion rhythm at 21 weeks of age. Although behavioural and tail lesion observations provided support to the assumption that a blunted rhythm indicates chronic stress, the biological significance of these cortisol results needs confirmation in future studies.     

Different mechanisms of phase delays and phase advances of the circadian rhythm in rat pineal N-acetyltransferase activity

The circadian rhythm in rat pineal N-acetyltransferase (NAT) activity, which drives the rhythm in melatonin production, is controlled by a pacemaker located in the suprachiasmatic nucleus of the hypothalamus. As the NAT rhythm has two well-defined phase markers--namely, the time of the evening activity rise and of the morning decline--it is suitable for studies of the entrainment of the pacemaker by environmental light. Phase delays of the NAT rhythm proceed more rapidly than phase advances. One day after a brief light pulse applied before midnight, or after a delay in evening lights-off, or a delay of a light-dark (LD) cycle, phase delays of the evening NAT rise result in almost corresponding delays of the morning NAT decline. Consequently, the NAT rhythm is phase-shifted, but its pattern does not change. One day after a brief light pulse applied past midnight, or after bringing forward morning lights-on, or after an advance of an LD cycle, the morning NAT decline is phase-advanced, but the evening rise is not phase-advanced at all or may even by phase-delayed. Consequently, the phase relationship between the evening NAT activity onset and the morning offset may be compressed considerably, and it may take several transient cycles before phase advances of the morning NAT decline are followed by corresponding advances of the evening NAT rise. Due to the phase-delaying effect of evening light on the NAT rise and to the phase-advancing effect of morning light on the NAT decline, the phase relationship between the NAT rise and the decline is compressed on long days and decompressed on short days. Different phase shifts of the evening NAT rise and of the morning decline, even in opposite directions, are consistent with the hypothesis of a complex, two-component (evening-morning, or E-M) pacemaker controlling the NAT rhythm. As the E-M phase relationship determines duration of the high night melatonin production, and the duration of the nocturnal melatonin pulse may convey information on daylength, the data are consistent with the internal coincidence model for photoperiodic time measurement.     

A method to evaluate dynamics and periodicity of hormone secretion

Spontaneous hormone secretory dynamics include tonic and pulsatile components and a number of periodic processes. Circadian variations are usually found for melatonin, TSH and GH, with peak secretions at night, and in cortisol secretion, which peaks in the morning. Free thyroxine (FT4) and insulin-like growth factor (IGF)1 levels do not always change with circadian rhythmicity or show only minor fluctuations. Fractional variations explore the dynamics of secretion related to time intervals, and the rate of change in serum levels represents a signal for the receptorial system and the target organ. We evaluated time-related variations and change dynamics for melatonin, cortisol, TSH, FT4, GH and IGF1 levels in blood samples obtained every 4 h for 24 h from eleven healthy males, ages 35-53 years (mean ? SE 43.6 ± 1.7). Nyctohemeral (i.e., day-night) patterns of hormone secretion levels and the fractional rate of variation between consecutive 4-hourly time-qualified hormone serum levels (calculated as percent change from time 1 to time 2) were evaluated for circadian periodicity using a 24 and 12-h cosine model. A circadian rhythm was validated for serum level changes in cortisol with peaks of the 24-h cosine model at 07:48 h, and melatonin, TSH and GH, with phases at 01:35 h, 23:32 h, and 00:00 h, respectively. A weak, but significant, 12-h periodicity was found for FT4 serum levels, with minor peaks in the morning (10:00 h) and evening (22:00 h), and for IGF1, with minor peaks in the morning (07:40 h) and evening (19:40 h). Circadian rhythmicity was found in the 4-hourly fractional variations with phases of increase or surge at 02:00 h for cortisol, 22:29 h for melatonin, 05:14 h for FT4, and 21:19 h for GH. A significant 12-h periodicity was found for the 4-hourly fractional variations of TSH with two peaks in the morning (decrease or drop at 04:42 h) and afternoon (surge at 16:28 h), whereas IGF1 fractional variation changes did not show a significant rhythmic pattern. In conclusion, the calculation of the time-qualified fractional rate of variation allows evaluation of the dynamics of secretion and the specification of the timepoint(s) of maximal change of secretion, not only for hormones whose secretion is characterized by a circadian pattern of variation, but also for hormones that show no circadian or only weak ultradian (12 h) variations (i.e., FT4).     

Variable sensitivity to the glucocorticoid activity of cortisol in patients with primary adrenal insufficiency: assessment with ACTH profiles

Our aim was to investigate the usefulness of circulating levels of adrenocorticotropic hormone (ACTH) and also salivary cortisol to monitor cortisone substitution in patients with Addison's disease. 13 patients with primary adrenal insufficiency (8 women and 5 men, age 44 ± 11 years) received 12.5 mg cortisone acetate orally at 16:00 h and 25 mg at 07:00 h. Blood samples for cortisol and ACTH analysis were drawn every hour for 24 h, and also every half hour between 07:00 and 12:00 h. Samples for salivary cortisol were collected in parallel. Total ACTH levels showed large inter-individual variations and a diurnal rhythm with a nadir in the early evening at 19:00 (median 19 ng/l, range 2-434 ng/l) and high levels in the early morning, with a peak around 07:30 (median 844 ng/l, range 45-2,249 ng/l). Plasma cortisol concentrations showed 2 peaks distinct in time, but variable in height, 1-2 h after intake of cortisone. Plasma cortisol correlated significantly with ln(ACTH) at 17:00 h (r=-0.56), at 10:00 h (r=-0.51), and at 10.30 h (r=-0.57). When tested at different time points, ln(ACTH) at 10:00 to 12:00 h was negatively correlated with plasma cortisol between 08:30 and 12:00 h. Plasma cortisol was highly correlated to ln(salivary cortisol) most of the time points measured, but 30-60 min after intake of cortisone acetate the correlation disappeared. In conclusion, the large interindividual variation in ACTH levels most likely indicates varying sensitivity to cortisol with a need for individualized dosing schemes. Furthermore ACTH-determinations may be useful for dose titration of cortisol.