Cortisol Secretion Rate Research Articles

Cortisol Response to Operative Stress With Anesthesia in Healthy Children

Supraphysiological "stress dosing" is generally given to adrenally insufficient patients undergoing operative procedures and/or general anesthesia. However, the normal responses of cortisol to surgery are poorly documented, especially in small children. Recent studies in adults suggest that massive glucocorticoid dosing is not needed, especially in minimally invasive surgery. We sought to characterize the normal cortisol secretion rate in healthy children undergoing minimally and moderately invasive urological procedures. This was a prospective observational study conducted at a tertiary referral center. Thirty healthy children, ages 5 months to 6 years, were studied undergoing elective urological procedures. Procedures were performed by a single surgeon; anesthesia was by a standard protocol. Sera were obtained at 5 points: iv catheter placement, intubation, 50% completion of surgery, anesthesia reversal, and 1 hour postoperative. Cortisol and cortisone were quantitated by liquid chromatography-tandem mass spectrometry. Group mean cortisol values ranged from 4.21 to 5.71 μg/dL across the 5 time points; none of these mean values differed significantly (P < .05). There were no differences according to age, time of procedure, caudal anesthesia, and moderate vs minimally invasive procedures; 3 patients had higher values. There was a modest diminution in cortisone across the 5 time points. Minimal and moderately invasive urological procedures do not result in a cortisol stress response in healthy children. Peak cortisol levels were seen 1 hour postoperatively. These data suggest that current guidelines for stress dosing in adrenally insufficient patients substantially exceed physiological requirements during minimally invasive procedures.

Relation of inflammation and liver function with the plasma cortisol response to adrenocorticotropin in early lactating dairy cows

In this study we examined the relationship between cortisol and inflammatory status in early lactating dairy cows after a stimulation test of the adrenal cortex. Twenty-four cows were grouped into quartiles (6 cows per each quartile) in accordance with the liver activity index (based on plasma concentration of negative acute phase proteins in early lactation); the quartiles were lower (LO; cows with the lowest liver functionality), intermediate lower, intermediate upper, and upper (UP; cows with the highest liver functionality). Each cow was injected i.v. with 20µg of a synthetic analog of ACTH at 35d in milk (DIM). Blood samples were taken to assess inflammatory status, and at 0, 30, and 60min after ACTH challenge to measure total cortisol. The free cortisol fraction was analyzed in the LO and UP quartiles and the bound cortisol fraction was estimated as the difference between total and free cortisol. The LO, in comparison with the other quartiles, suffered a more severe inflammatory status, with the highest values of haptoglobin, reactive oxygen metabolites, and total nitric oxide metabolites and the lowest concentration of direct or indirect markers of negative acute phase proteins. The cows in the LO quartile had the highest values of plasma nonesterified fatty acids and β-hydroxybutyrate at 7 DIM, suggesting a more severe body lipid mobilization. The LO quartile cows showed the highest frequency of health problems and the lowest milk yield in the first 35 DIM. Thirty minutes after the ACTH treatment, the concentration of total cortisol was lower in LO in comparison to other groups. Similarly, the bound cortisol fraction was lower in LO versus UP. The adrenal response appeared inversely related with health status after calving (e.g., lower in LO cows, experiencing the most severe inflammatory status). The lower increase in cortisol after the ACTH challenge in cows with greater inflammation (LO quartile) seems a consequence of the lower availability of cortisol-binding globulin synthetized by the liver, but other mechanisms can be involved (e.g., rate of cortisol production, secretion, and metabolic clearance). Our data provide evidence that inflammation and metabolic changes reduce the concentration of circulating plasma cortisol during an acute stress. Hence, the acute phase response in dairy cows should be taken into account to interpret the results obtained from stimulation tests of the adrenal cortex.

Estimation of Maximal Cortisol Secretion Rate in Healthy Humans

Cortisol secretion is related to ACTH concentration by a sigmoidal dose-response curve, in which high ACTH concentrations drive maximal cortisol secretion rates (CSR(max)). We sought to estimate CSR(max) and free cortisol half-life in healthy humans (n = 21) using numerical methods applied to data acquired during cosyntropin (250 μg) stimulation. We also evaluated the effect of overnight dexamethasone (DEX; 1 mg) vs. placebo on estimates of CSR(max) and free cortisol half-life. This study was a double-blind, placebo-controlled, randomized order of overnight DEX vs. placebo, cosyntropin (250 μg) stimulation with frequent serum cortisol sampling and computer-assisted numerical analysis. The study was conducted at a single academic medical center. Twenty-one healthy adult subjects (15 females and six males), mean aged 46 yr, participated in the study. Intervention in the study included DEX vs. placebo pretreatment, cosyntropin (250 μg) iv with frequent cortisol sampling. CSR(max) and free cortisol half-life estimates, R² for goodness of fit, were measured. Mean ± sd CSR(max) was 0.44 ± 0.13 nm/second, with free cortisol half-life of 2.2 ± 1.1 min. DEX did not significantly affect estimates of CSR(max) or free cortisol half-life. Our model accounts for most of the variability of measured cortisol concentrations (overall R² = 90.9 ±11.0%) and was more accurate (P = 0.004) during DEX suppression (R² = 94.6 ± 4.6%) compared with placebo (R² = 87.2 ± 8.7%). Application of a mass-action model under conditions of cosyntropin stimulation provides a relatively simple method for estimation CSR(max) that accurately predicts measured cortisol concentrations. DEX administration did not significantly affect estimates of CSR(max) or free cortisol half-life.

Overnight ACTH-cortisol dose responsiveness: comparison with 24-h data, metyrapone administration and insulin-tolerance test in healthy adults

To estimate the dose dependence of endogenous ACTH stimulation of adrenal cortisol secretion overnight. Ten-minute sampling for ACTH and cortisol over 8 and 24 h (n = 17), after metyrapone administration (n = 6), during an insulin-tolerance test (n = 7). Healthy adults. ACTH dose-responsive estimates. Twenty-four hour ACTH-cortisol concentration pairs yielded an estimated EC(50) (one-half maximally stimulatory ACTH concentration) of 5·1 (2·2-9·5) pmol/l [median (range)]. This did not differ from EC(50) s based on 8- or 6-h data [5·9 (3·5-11) and 7·5 (3·7-41) pmol/l] in the same individuals. ACTH efficacy (maximally stimulatable cortisol secretion rate) was 8·4 (3·1-20), 11 (5·9-24) and 15 (5·9-22) nmol/l/min, when calculated over 24, 8 and 6 h, respectively (P = NS). Adrenal sensitivity (slope term) was also consistent across sampling durations, viz. 14 (1·3-95), 18 (1·3-64) and 20 (1·3-64) slope units. Compared with placebo, metyrapone reduced ACTH efficacy from 11 (6·2-62) to 2·8 (1·5-4·5) nmol/l/min for cortisol (n = 9, P < 0·001), while increasing ACTH efficacy for 11-desoxycortisol from 2·3 (0·9-2·9) to 99 (70-218) nmol/l/min (n = 6, P < 0·01), thus affirming face validity. Combined ACTH and cortisol responses to hypoglycaemia allowed an estimate of ACTH efficacy of 28 (22-81) nmol/l/min, compared with the control value of 8·7 (5·6-26), suggesting enhanced adrenal responsiveness. The results suggest that endogenous ACTH-adrenal drive can be approximated from overnight 8-h sampling of paired ACTH and cortisol concentrations. This strategy may have merit in clinical research in childhood, pregnancy, anxiety states and frail elderly individuals, when ACTH injections are not desired.

Endogenous ACTH Concentration-Cortisol Secretion Dose Analysis Unmasks Decreased ACTH Potency in Cushing's Disease with Restoration after Successful Pituitary Adenomectomy

The relationship between circulating ACTH levels and cortisol secretion in Cushing's disease is not precisely known. Chronic ACTH hyperstimulation leads to decreased adrenal potency and is restored after normalization of ACTH secretion. Subjects included 20 patients with Cushing's disease, eight patients in long-term remission, and 36 healthy controls. ACTH and cortisol secretion rates and analytical dose-response estimates of endogenous ACTH efficacy (maximal cortisol secretion), dynamic ACTH potency, and adrenal sensitivity (slope term) from 24-h ACTH-cortisol profiles were evaluated. Both basal and pulsatile secretion of ACTH and cortisol were increased in patients with active disease but normal in cured patients. ACTH, but not cortisol pulse frequency, was amplified in patients and restored after successful surgical treatment. ACTH EC(50), an inverse measure of potency, was higher during pulse onset in Cushing's disease (59 ± 7.4 ng/liter) than in controls (20 ± 3.7 ng/liter) (P < 0.0001) and remitted patients after surgery [15 ± 3.2 ng/liter, P value not significant (NS) vs. controls] and during pulse recovery phases [128 ± 18 (P <0.0001), 70 ± 8.4, and 67 ± 17 ng/liter (NS vs. controls), respectively]. Efficacy was increased in active disease and normalized after surgical treatment [patients, 38 ± 8.3 nmol/liter · min, vs. controls, 21 ± 2.3 nmol/liter · min (P <0.0001), and cured patients, 15 ± 3.2 nmol/liter · min (NS vs. controls)]. Sensitivity to endogenous ACTH did not differ among the three groups. The adrenal gland in Cushing's disease exhibits decreased responsiveness to submaximal ACTH drive and amplified efficacy, with unchanged sensitivity. These target-gland abnormalities are reversible in long-term remission after pituitary surgery.

Diurnal salivary cortisol concentrations in Parkinson&amp;rsquo;s disease: increased total secretion and morning cortisol concentrations

Background:Parkinson’s disease (PD) is a chronic neurodegenerative disorder. There is limited knowledge about the function of the hypothalamic-pituitary-adrenal axis in PD. The primary aim of this prospective study was to analyze diurnal salivary cortisol concentrations in patients with PD and correlate these with age, gender, body mass index (BMI), duration of PD, and pain. The secondary aim was to compare the results with a healthy reference group.Methods:Fifty-nine PD patients, 35 women and 24 men, aged 50–79 years, were recruited. The reference group comprised healthy individuals matched for age, gender, BMI, and time point for sampling. Salivary cortisol was collected at 8 am, 1 pm, and 8 pm, and 8 am the next day using cotton-based Salivette® tubes and analyzed using Spectria® Cortisol I125. A visual analog scale was used for estimation of pain.Results:The median cortisol concentration was 16.0 (5.8–30.2) nmol/L at 8 am, 5.8 (3.0–16.4) at 1 pm, 2.8 (1.6–8.0) at 8 pm, and 14.0 (7.5–28.7) at 8 am the next day. Total secretion and rate of cortisol secretion during the day (8 am–8 pm) and the concentration of cortisol on the next morning were lower (12.5 nmol/L) in the reference group. No significant correlations with age, gender, BMI, duration of PD, Hoehn and Yahr score, Unified Parkinson’s Disease Rating Scale III score, gait, pain, or cortisol concentrations were found.Conclusion:The neurodegenerative changes in PD does not seem to interfere with the hypothalamic-pituitary-adrenal axis. Salivary cortisol concentrations in PD patients were increased in the morning compared with the reference group, and were not influenced by motor dysfunction, duration of disease, or coexistence of chronic or acute pain.

Adrenal Extracellular Matrix Scaffolds Support Adrenocortical Cell Proliferation and FunctionIn Vitro

Transplantation of functional adrenal cortex cells could reduce morbidity and increase the quality of life of patients with adrenal insufficiency. Our aim was to determine whether adrenal extracellular matrix (ECM) scaffolds promote adrenocortical cell endocrine function and proliferation in vitro. We seeded decellularized porcine adrenal ECM with primary human fetal adrenocortical (HFA) cells. Adrenocortical function was quantified by cortisol secretion of HFA-ECM constructs after stimulation with adrenocorticotropic hormone. Proliferation was assessed by adenosine triphosphate assay. HFA-ECM construct morphology was evaluated by immunofluorescence microscopy and scanning electron microscopy. Adrenal HFA-ECM constructs coated with laminin were compared to uncoated constructs. Laminin coating did not significantly affect HFA morphology, proliferation, or function. We demonstrated HFA cell attachment to adrenal ECM scaffolds. Cortisol production and HFA cell proliferation were significantly increased in HFA-ECM constructs compared to controls (p < 0.05), and cortisol secretion rate per cell is comparable to that of human adult and fetal explants. We conclude that adrenal ECM supports endocrine function and proliferation of adrenocortical cells in vitro. Adrenal ECM scaffolds may form the basis for biocompatible tissue-engineered adrenal replacements.

Relationships among salivary immunoglobulin A, lactoferrin and cortisol in basketball players during a basketball season

The aim of this study was to examine the changes and relationships of immune and stress parameters of basketball players during a basketball season. Eight members of National Taichung University basketball team volunteered to participate. Saliva samples were collected at rest and before the start of practice or competition at seven time points during the intense training, competition and recovery period. Salivary immunoglobulin A (sIgA), cortisol, and lactoferrin were measured during training and competition period and compared with those measured at the fourth recovery week. Relationships among immune and stress parameters were evaluated. Compared with those detected at the fourth recovery week, significant decreases in secretion rates and absolute concentrations of sIgA and lactoferrin were observed at times of intense training and competition. In addition, significant increases in secretion rates and absolute concentrations of salivary cortisol were observed during intense training and competition period and the first week of recovery. Moreover, a significant inverse correlation (r=-0.28; P<0.05) that existed between secretion rates of sIgA and cortisol as well as a positive correlation (r=0.32; P<0.05) that existed between secretion rates of sIgA and lactoferrin was measured. Our results demonstrated that the secreted cortisol was induced and the mucosal immunity of the participants was suppressed during the basketball season. The inverse correlation existed between secretion rates of sIgA and cortisol may indicate a possible role of cortisol in the strenuous exercise-induced immunosuppression. Our results also suggest that a delicate balance may exist between mucosal innate and adaptive immune responses.

Cortisol release, heart rate, and heart rate variability in transport-naive horses during repeated road transport

Domestic animals are often repeatedly exposed to the same anthropogenic stressors. Based on cortisol secretion and heart rate, it has been demonstrated that transport is stressful for horses, but so far, changes in this stress response with repeated road transport have not been reported. We determined salivary cortisol concentrations, fecal cortisol metabolites, cardiac beat-to-beat (RR) interval, and heart rate variability (HRV) in transport-naive horses (N = 8) transported 4 times over a standardized course of 200 km. Immunoreactive salivary cortisol concentrations always increased in response to transport ( P < 0.001), but cortisol release decreased stepwise with each transport ( P < 0.05). Concentrations of fecal cortisol metabolites increased from 55.1 ± 4.6 ng/g before the first transport to 161 ± 17 ng/g the morning after ( P < 0.001). Subsequent transport did not cause further increases in fecal cortisol metabolites. In response to the first transport, mean RR interval decreased with loading of the horses and further with the onset of transport (1551 ± 23, 1304 ± 166, and 1101 ± 123 msec 1 d before, immediately preceeding, and after 60–90 min of transport, respectively; P < 0.05). Decreases in RR interval during subsequent transports became less pronounced ( P < 0.001). Transport was associated with a short rise in the HRV variable standard deviation 2 ( P < 0.001 except transport 1), indicating sympathetic activation. No consistent changes were found for other HRV variables. In conclusion, a transport-induced stress response in horses decreased with repeated transport, indicating that animals habituated to the situation, but an increased cortisol secretion remained detectable.

Dose-response downregulation within the span of single interpulse intervals

Pituitary ACTH drives adrenal glucocorticoid (cortisol) pulses via a time-delayed asymptotic dose-response process. To test the postulate that ACTH stimulates cortisol secretion dynamically (unequally during the initiation and termination of a cortisol secretory burst), a mathematical formalism was developed in which dose-response hysteretic shifts were allowed, but not required, within the time evolution of ACTH-cortisol pulse pairs. A dual-waveform deconvolution model was used to quantify cortisol secretion rates and reconstruct ACTH concentration profiles in 28 healthy adults previously sampled every 10 min for 24 h in the unstressed state (8,120 measurements). ACTH concentration-cortisol secretion dose-response functions were then estimated in each subject 1) without hysteresis (base model) and with allowances for possible hysteresis in 2) ACTH potency, 3) adrenal sensitivity, and 4) ACTH efficacy. Model residual error was 40% lower in the potency and sensitivity models and 20% lower in the efficacy model than in the base model (P < 0.001). Mean time shifts for inferable hysteretic inflection were model-independent, i.e., grand mean (95% confidence interval) 22 (12-39) min after the onset of a cortisol secretory burst. Half-maximally effective ACTH concentrations (EC(50)) differed before and after hysteretic inflection within individual pulses: 1) 9.4 and 54 ng/l in the potency model (P < 0.001) and 2) 8.9 and 123 ng/l in the sensitivity model (P < 0.001) compared with 16 ng/l in the no-hysteresis model (P < 0.001). In the efficacy-shift model, estimated maximal ACTH drive varied by 17-fold within cortisol secretory bursts (from 22 to 1.3 nmol.l(-1).min cortisol secretion(-1), P < 0.001). The collective results introduce the basis for modeling the dynamics of rapid, reversible physiological downregulation within the span of single interpulse intervals in vivo. This construct should have utility in parsing mechanisms of physiological regulation in other integrative systems.

Increased Hypothalamic-Pituitary-Adrenal Axis Activity in Huntington’s Disease

Abstract Context: Huntington’s disease (HD) is a fatal hereditary neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction could contribute to a number of HD signs and symptoms; however, no data are available on cortisol diurnal variations and secretory dynamics in HD patients. Objective: The aim of the study was to perform a detailed analysis of HPA axis function in HD patients in relation to clinical signs and symptoms. Design, Setting, and Participants: Twenty-four-hour cortisol secretion was studied in eight early-stage, medication-free HD patients and eight age-, sex-, and body mass index-matched controls in a clinical research laboratory. Cortisol levels were measured every 10 min. Main Outcome Measures: Multiparameter autodeconvolution and cosinor regression were applied to quantify basal, pulsatile, and total cortisol secretion rates as well as diurnal variations in cortisol levels. Results: Total cortisol secretion rate and the amplitude of the diurnal cortisol profile were both significantly higher in HD patients compared with controls (3490 ± 320 vs. 2500 ± 220 nmol/liter/24 h, P = 0.023; and 111 ± 14 vs. 64 ± 8 nmol/liter, P = 0.012, respectively). Cortisol concentrations in patients were particularly increased in the morning and early afternoon period. In HD patients, mean 24-h cortisol levels significantly correlated with total motor score, total functional capacity, as well as body mass index. Conclusions: HPA axis hyperactivity is an early feature of HD and is likely to result from a disturbed central glucocorticoid feedback due to hypothalamic pathology. HPA axis dysfunction may contribute to some signs and symptoms in HD patients.

Increased Hypothalamic-Pituitary-Adrenal Axis Activity in Huntington’s Disease

Huntington's disease (HD) is a fatal hereditary neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction could contribute to a number of HD signs and symptoms; however, no data are available on cortisol diurnal variations and secretory dynamics in HD patients. The aim of the study was to perform a detailed analysis of HPA axis function in HD patients in relation to clinical signs and symptoms. Twenty-four-hour cortisol secretion was studied in eight early-stage, medication-free HD patients and eight age-, sex-, and body mass index-matched controls in a clinical research laboratory. Cortisol levels were measured every 10 min. Multiparameter autodeconvolution and cosinor regression were applied to quantify basal, pulsatile, and total cortisol secretion rates as well as diurnal variations in cortisol levels. Total cortisol secretion rate and the amplitude of the diurnal cortisol profile were both significantly higher in HD patients compared with controls (3490 +/- 320 vs. 2500 +/- 220 nmol/liter/24 h, P = 0.023; and 111 +/- 14 vs. 64 +/- 8 nmol/liter, P = 0.012, respectively). Cortisol concentrations in patients were particularly increased in the morning and early afternoon period. In HD patients, mean 24-h cortisol levels significantly correlated with total motor score, total functional capacity, as well as body mass index. HPA axis hyperactivity is an early feature of HD and is likely to result from a disturbed central glucocorticoid feedback due to hypothalamic pathology. HPA axis dysfunction may contribute to some signs and symptoms in HD patients.

Reduced Glucocorticoid Production Rate, Decreased 5α-Reductase Activity, and Adipose Tissue Insulin Sensitization After Weight Loss

ObjectiveThe epidemic of obesity, insulin resistance and type 2 diabetes has heightened the need to understand mechanisms that contribute to their pathogenesis. Increased endogenous glucocorticoid (GC) production has been implicated based upon parallels with Cushing’s syndrome. We have assessed the impact of weight loss upon GC secretion and metabolism (notably 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 5α-reductase (5αR) activity) and insulin sensitivity.Research Design and Methods20 obese volunteers were investigated before and after weight loss. Patients underwent hyperinsulinemic euglycemic clamps with simultaneous adipose microdialysis and oral cortisone acetate administration. Changes in GC secretion and metabolism were assessed using 24h urine collections.ResultsBefore weight loss, fat mass correlated with GC secretion rate (total fat, R=0.46, p<0.05; trunk fat, R=0.52, p<0.05); however, GC secretion rate was inversely related to insulin sensitivity (R=-0.51, p<0.05). Hyperinsulinemia failed to suppress adipose tissue interstitial fluid glycerol release (180±50 (basal) vs. 153±10μmol (steady state), p=ns). After oral cortisone (25mg), cortisol concentrations within adipose interstitial fluid increased (4.3±1.1 vs. 14.2±2.6nmol/L, p<0.01), but glycerol concentrations didn’t change. Following weight loss, insulin sensitivity increased. Consistent with insulin sensitization, adipose tissue interstitial fluid glycerol concentrations fell under hyperinsulinemic conditions (186±16 vs. 117±9μmol, p<0.05). GC secretion decreased (11751±1520 vs. 7464±937μg/24h, p<0.05) as did 5αR activity (5αTHF/THF ratio 1.41±0.16 vs. 1.12±0.17, p<0.005).ConclusionsObesity is associated with insulin resistance within adipose tissue and increased cortisol secretion rates, both are reversed with weight loss. Reduced 5αR activity following weight loss may decrease hypothalamo-pituitary-adrenal (HPA) axis activation and reduce GC metabolite production.

Response variability of salivary cortisol among older adults under psychological stress

In this study, a quasi-experimental design with repeated measures was used to compare anxious (n = 129) and nonanxious (n = 186) older adults on the cortisol secretion rate attributable to an experimental stressor. Our results support the hypothesis that a first-order longitudinal factor model appropriately describes the cortisol concentration in three saliva samples collected at two experimental times. The model tested explained between 82.6 and 98.0% of the variance in cortisol concentration of the respondent's saliva samples at T1, and between 55.4% and 78.4% at T2. In the nonanxious group ((State-Trait Anxiety Inventory) STAI < 42), the magnitude of the experiment-related cortisol reactivity was, respectively 51 and 33% higher than the respondent's baseline reactivity level at both T1 and T2. By contrast, in the anxious group (STAI ≥ 42), our results showed no significant gradient in the magnitude of the cortisol reactivity at either time. This result was interpreted to be in agreement with the helplessness reaction hypothesis. These results suggest that salivary cortisol is a valid measure that is sensitive to experimental stress, and may therefore, be useful in examining physiological response to stress.

NUMERICAL SOLUTION FOR CORTISOL EQUILIBRIUM AND MAXIMAL CORTISOL SECRETION RATES IN HUMAN SEPTIC SHOCK AND HEALTHY CONTROL SUBJECTS.

Septic shock (SS) is associated with an increase in total and free cortisol along with a disproportionate increase in percent free cortisol, due in part to decreased serum concentrations of cortisol-binding globulin (CBG) and albumin. Relative adrenal insufficiency (RAI) is often seen in septic shock and is biochemically defined by a cortisol increment Objective Keenan et al proposed a set of three differential equations describing a dynamic model for free cortisol secretion and clearance rates, which incorporates the reactions of free cortisol with CBG and albumin, under non-steady-state conditions. We sought to assess maximal cortisol secretion rates in SS and in control subjects using numerical techniques to solve for cortisol equilibrium in the serum compartment and for cortisol secretion and clearance rates. Methods Plasma total and free cortisol, serum CBG, and albumin were measured in subjects with SS (n = 45), subjects with sepsis (S, n = 19), and in healthy controls (HC, n = 10) at 0, 30, and 60 minutes after 250 μg cosyntropin. Numerical solution for cortisol secretion rates used group-specific KA determined by least squares solution and assumed a uniform, maximal cortisol secretion rate to provide a least squares solution for secretion and clearance to fit observed data points. Results The group-specific KA was significantly higher in SS versus S and HC (148, 99, and 78 μM, p Conclusions SS and RAI are associated with a reversible increase in KA, contributing to an increase in percent free cortisol. Maximal cortisol secretion rates are elevated in SS, including RAI subjects. The distribution of the normal range of maximal secretion rates (CV = 48%) suggests that application of numerical solution to non-steady-state conditions, such as the cosyntropin stimulation test, may be useful in distinguishing absolute and relative adrenal insufficiency.

The Adrenocorticotropin Stimulation Test: Contribution of a Physiologically Based Model Developed in Horse for Its Interpretation in Different Pathophysiological Situations Encountered in Man

The present study aimed to characterize the adrenal response to ACTH. A model was developed that coupled the nonlinear disposition of cortisol with a physiologically based model for cortisol secretion by the adrenals. It was assumed that the response to ACTH resulted from two mechanisms: a stimulation of the cortisol secretion rate and control of the duration of the secretion. Seven dose levels of ACTH were tested in horses, a species similar to man as regards adrenal function. The main result was that the secretion rate of the adrenal gland can be modelized by a zero order process that is maximal for a relatively low dose of ACTH (0.1 microg/kg). Beyond this dose, the increasing adrenal gland response is only due to the prolongation of the time of its secretion. The consequences of these different features were explored by simulation to reproduce classical pathophysiological situations encountered in man. Our model was able to reproduce and simply explain many adrenal gland responses that are dimmed by the different nonlinearities of the system.

Salivary IgA Response to Intermittent and Continuous Exercise

Current evidence would support a view that intense exercise increases whereas moderate exercise reduces the susceptibility to illness, predominately upper respiratory tract infections. Concentrations of IgA and cortisol in saliva may be used to reflect changes in immune function. The aim of this study was to determine if the type of exercise (soccer-specific intermittent or continuous exercise at the same average work-rate and duration) affects salivary IgA (s-IgA) and cortisol responses. In a randomized, counterbalanced design, eight healthy males completed two trials one week apart at the same time of day on a motorized treadmill. One session entailed soccer-specific intermittent exercise, the other involved continuous exercise at the same overall work-rate. Diet and activity were standardized for 48 hours prior to and following each trial. Unstimulated saliva samples were collected via passive expectoration during the week prior to commencement of exercise, before, at half-time, immediately post-exercise, and 6 hours, 24 hours, and 48 hours post-exercise. No significant difference was observed in heart rate between the two exercise conditions (Intermittent: 142 +/- 14; Continuous: 141 +/- 16 beats x min (-1)). Average rating of perceived exertion was higher (p < 0.05) in intermittent exercise (11.9 +/- 0.8) than during continuous exercise (10.8 +/- 1.2). The pattern of change in salivary responses, including solute secretion rate, IgA concentration, IgA secretion rate, IgA to osmolality ratio, cortisol, and cortisol secretion rate did not differ between the two trials (p > 0.05). Concentrations of s-IgA for the intermittent and continuous protocols were 131.6 +/- 61.2 vs. 146.4 +/- 107.6 before, 148.4 +/- 82.5 vs. 229.2 +/- 159.6 after, and 125 +/- 78.7 vs. 131.1 +/- 80.7 48 h post-exercise, respectively. Saliva flow rate decreased and osmolality increased significantly across all time points (p < 0.05). In conclusion, soccer-specific intermittent exercise did not suppress the salivary IgA response or alter cortisol secretion compared to continuous exercise performed at the same overall work-rate.

Growth in congenital adrenal hyperplasia

Individuals with congenital adrenal hyperplasia (CAH) are shorter, on an average, than the general population. A recent meta analysis of final height in CAH indicated that the height deficit is typically 1 to 2 standard deviations below the mean in both males and females. Growth in CAH due to 21-hydroxylase deficiency is influenced by a number of factors, related both to the underlying disease and its treatment. In general, males with the simple virilising form have the poorest height prognosis. This relates in part to late diagnosis and treatment and the bone age advancement seen in individuals with untreated postnatal androgen excess. Obesity in CAH patients also appears to be correlated with reduced height potential. Glucocorticoid treatment which is vital for cortisol replacement, prevention of adrenal crises and androgen suppression, results in growth inhibition when administered in larger doses. Current evidence suggests that infancy and peripubertal periods are the time periods where height outcome is most sensitive to glucocorticoid dose. More recent estimates of physiological cortisol secretion rates indicate that standard cortisol replacement schedules may result in overtreatment. In addition, dose titration to achieve complete androgen suppression and normalization of 17-hydroxyprogesterone is likely to result in overtreatment and consequent growth impairment. Optimization of current treatment may lead to further improvements in height prognosis. The potential benefits of more complex treatment regimes, using aromatase inhibitors and antiandrogens, in combination with a reduced glucocorticoid dose remain uncertain.

Absence of Adrenocorticotropin (ACTH) Neurosecretory Dysfunction but Increased Cortisol Concentrations and Production Rates in ACTH-Replete Adult Cancer Survivors after Cranial Irradiation for Nonpituitary Brain Tumors

For the first time, physiological cortisol secretion has been studied in ACTH-replete adult cancer survivors to explore any discrepancy between stimulated (during insulin-induced hypoglycemia) and spontaneous cortisol secretion and, in particular, the possible existence of ACTH neurosecretory dysfunction that might explain the excessive fatigue suffered by some cancer survivors. Cortisol profiling at 20-min intervals over 24 h during the fed state was undertaken in 34 patients (10 females), aged 17-53.7 yr (median, 21.5 yr), 2-29 yr (median, 11.5 yr) after receiving conventional cranial irradiation for nonpituitary brain tumors or leukemia (n = 5) and in 33 age-, gender-, and body mass index-matched normal controls, of whom 23 patients and 17 controls were also profiled in the last 24 h of a 33-h fast. The fed profile mean cortisol concentration (mean +/- sem) was significantly increased (by 14%) in the patients compared with that in normal subjects (213 +/- 6.9 vs. 187 +/- 6.7 nmol/liter; P = 0.009), with all individual values above the lowest seen in normal subjects. Multiparameter deconvolution analysis revealed a parallel increase (by 20%) in cortisol secretion rates (1.8 +/- 0.09 vs. 1.5 +/- 0.08 nmol/liter.min; P = 0.03) due to selective augmentation of the cortisol mass released per burst with no changes in burst frequency (12/24 h) or half-life. No significant differences were observed between males and females, after short-term fasting, or between female patients and normal females. Thus, in the light of total group comparisons, male patients had even higher values than normal males, and more so during fasting (mean cortisol and cortisol secretion increased by 20 and 29% in the fed state and by 41 and 32% in the fasting state, respectively; P < 0.05). This study has demonstrated that radiation-induced ACTH neurosecretory dysfunction does not exist and, thus, resolved the clinical dilemma as to whether cortisol replacement should be considered in those patients with excessive fatigue and normal stimulated cortisol responses. On the contrary, cranial irradiation causes activation of the corticotrope-adrenal axis, and in the absence of ACTH deficiency, this activation is manifested by parallel increases in circulating cortisol levels and cortisol production rates without any change in cortisol half-life. The lack of cortisol increase in female patients may be attributed to the adverse effect of their higher body mass index on cortisol secretion or may reflect a genuine gender dichotomy.

Joint synchrony of reciprocal hormonal signaling in human paradigms of both ACTH excess and cortisol depletion

The hypothalamo-pituitary-adrenal axis is a stress-adaptive neuroendocrine ensemble, in which adrenocorticotropin (ACTH) drives cortisol secretion (feedforward) and cortisol restrains ACTH outflow (feedback). Quantifying direction- and pathway-specific adjustments within this and other interlinked systems by noninvasive means remains difficult. The present study tests the hypothesis that forward and reverse cross-approximate entropy (X-ApEn), a lag-, scale-, and model-independent measure of two-signal synchrony, would allow quantifiable discrimination of feedforward (ACTH --> cortisol) and feedback (cortisol --> ACTH) control. To this end, forward X-ApEn was defined by employing serial ACTH concentrations as a template to appraise pair-wise synchrony with cortisol secretion rates and vice versa for reverse X-ApEn. Coupled hormone profiles included normal ACTH-normal cortisol, high ACTH-high cortisol, and high ACTH-low cortisol concentrations in 35 healthy subjects, 21 patients with tumoral ACTH secretion, and 9 volunteers given placebo and a steroidogenic inhibitor, respectively. We used forward and reverse X-ApEn analyses to identify marked and equivalent losses of feedforward and feedback linkages (both P < 0.001) in patients with tumoral ACTH secretion. An identical analytical strategy revealed that ACTH --> cortisol feedforward synchrony decreases (P < 0.001), whereas cortisol --> ACTH feedback synchrony increases (P < 0.001), in response to hypocortisolemia. The collective outcomes establish precedence for pathway-specific adaptations in a major neurohormonal system. Thus quantification of directionally defined joint synchrony of biologically coupled signals offers a noninvasive strategy to dissect feedforward- and feedback-selective adaptations in an interactive axis.