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Context: Hormones of the hypothalamic-pituitary-target gland axes are mostly investigated separately, whereas the interplay between hormones might be as important as each separate hormonal axis., Objective: Our aim is to determine the interrelationships between GH, TSH, ACTH, and cortisol in healthy older individuals., Design: We made use of 24-hour hormone serum concentrations assessed with intervals of 10 minutes from 38 healthy older individuals with a mean age (SD) of 65.1 (5.1) years from the Leiden Longevity Study. Cross-correlation analyses were performed to assess the relative strength between 2 24-hour hormone serum concentration series for all possible time shifts. Cross-approximate entropy was used to assess pattern synchronicity between 2 24-hour hormone serum concentration series., Results: Within an interlinked hormonal axis, ACTH and cortisol were positively correlated with a mean (95% confidence interval) correlation coefficient of 0.78 (0.74-0.81) with cortisol following ACTH concentrations with a delay of 10 minutes. Between different hormonal axes, we observed a negative correlation coefficient between cortisol and TSH of -0.30 (-0.36 to -0.25) with TSH following cortisol concentrations with a delay of 170 minutes. Furthermore, a positive mean (95% confidence interval) correlation coefficient of 0.29 (0.22-0.37) was found between TSH and GH concentrations without any delay. Moreover, cross-approximate entropy analyses showed that GH and cortisol exhibit synchronous serum concentration patterns., Conclusions: This study demonstrates that interrelations between hormones from interlinked as well as different hypothalamic-pituitary-target gland axes are observed in healthy older individuals. More research is needed to determine the biological meaning and clinical consequences of these observations., (© Endocrine Society 2019.)

Context: Factors that regulate physiological feedback by pulses of glucocorticoids on the hypothalamic-pituitary unit are sparsely defined in humans in relation to gluco- or mineralocorticoid receptor pathways, gender, age, and the sex steroid milieu., Objective: The objective of the study was to test (the clinical hypothesis) that glucocorticoid (GR) and mineralocorticoid (MR) receptor-selective mechanisms differentially govern pulsatile cortisol-dependent negative feedback on ACTH output (by the hypothalamo-pituitary unit) in men and women studied under experimentally defined T and estradiol depletion and repletion, respectively., Setting: The study was conducted at the Mayo Center for Translational Science Activities., Subjects: Healthy middle-aged men (n = 16) and women (n = 25) participated in the study., Interventions: This was a randomized, prospective, double-blind, placebo- and saline-controlled study of pulsatile cortisol infusions in low cortisol-clamped volunteers with and without eplerenone (MR blocker) and mifepristone (GR blocker) administration under a low and normal T and estradiol clamp. During frequent sampling, a bolus of CRH-arginine vasopressin was infused to assess corticotrope responsiveness. Analytical Methods and Outcomes: Deconvolution and approximate entropy of ACTH profiles were measured., Results: Infusion of cortisol (but not saline) pulses diminished ACTH secretion. The GR antagonist, mifepristone, interfered with negative feedback on both ACTH burst mass and secretion regularity. Eplerenone, an MR antagonist, exerted no detectable effect on the same parameters. Despite feedback imposition, CRH-arginine vasopressin-stimulated ACTH secretion was also increased by mifepristone and not by eplerenone. Withdrawal vs addback of sex steroids had no effect on ACTH secretion parameters. Nonetheless, ACTH secretion was greater (P = .006) and more regular (P = .004) in men than women., Conclusion: Pulsatile cortisol feedback on ACTH secretion in this paradigm is mediated by the glucocorticoid receptor, in part acting at the level of the pituitary, and influenced by sex.

Background: Prolactin (PRL) has many effects in animals and man. For example, it regulates fat mass in fish, birds, and mammals. In particular, the timing of the serum PRL acrophase in relation to the light-dark cycle or to serum cortisol in constant light conditions determines whether the fat mass increases or decreases, as part of the adaptation to seasons. The role of PRL in this respect has been less well studied in man., Hypothesis: We hypothesized that the timing of the PRL acrophase (time point of peak amplitude of the rhythm) with respect to that of cortisol may be correlated with fat mass [or body mass index (BMI) as proxy] in the human, as observed in animals., Subjects: Seventy-four subjects were available [mean age, 43 (22-77) yr; mean BMI, 26.8 (18.7-38.4) kg/m(2)]., Measures: Immunofluorometric PRL assay and cortisol RIA of 10-min blood samples collected for 24 h were followed by cosinor analysis for the estimation of the acrophase., Results: The time difference between the cortisol and PRL acrophases was positively correlated with BMI (P = 0.002), but not with sex, age, or season., Conclusion: In various species, a wide gap between the serum cortisol acrophase and that of PRL leads to fat storage. Our finding is consistent with this observation, although we used BMI as proxy. If an advance shift of the PRL acrophase in relation to that of cortisol is indeed responsible for increased fat mass in man, manipulating the PRL phase may offer an alternative means to treat obesity.

Background: The ACTH-cortisol axis in women is activated and associated with decreased ACTH potency, estimated by relating ACTH and cortisol pulse masses. Recently, a new accurate method for constructing the endogenous dose-response relationship was introduced, which is based on the relation between ACTH concentrations and associated cortisol secretion rates within cortisol bursts., Hypothesis: The endogenous dose-response relation between ACTH and cortisol in obesity is changed, leading to diminished responsiveness., Subjects: Twenty-five obese premenopausal women and 16 normal weight premenopausal women were studied by 10-min blood sampling for 24 h., Outcomes: ACTH and cortisol secretion rates, 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 quantified., Results: The initial potency (negative logarithm) was -7.83 ± 0.75 (mean ± s.e.m.) in obese women and -10.14 ± 1.08 in lean women (P=0.10), and the corresponding values for the recovery phase were -26.62 ± 2.21 and -36.67 ± 1.66 (P=0.004). The sensitivity (curve slope) amounted to 0.468 ± 0.05 in obese women and 0.784 ± 0.09 in normal weight women (P=0.004). The efficacy (maximal value) was 17.6 ± 4.9 nmol/l per min in obese women and 26.3 ± 3.8 nmol/l per min in normal weight women (P=0.009). Basal secretion rate, inflection point, and EC(50) values were not different. Bromocriptine or acipimox did not change the dose-response curve., Conclusion: The ACTH-cortisol relation in obesity in women is characterized by decreased sensitivity and efficacy, thus explaining non-elevated serum cortisol concentrations despite increased plasma ACTH levels.

Transsphenoidal surgery (TS) is the treatment of choice for many pituitary tumors. Because TS may cause pituitary insufficiency in some of these patients, early postoperative assessment of pituitary function is essential for appropriate endocrine management. The aim of our study was to evaluate the clinical relevance of the CRH-stimulation test in assessing postoperative pituitary-adrenal function. We performed a retrospective analysis of 144 patients treated by TS between January 1990 and November 2009, in whom a CRH-test and a second stimulation test was performed to assess adrenal function during follow-up. Patients with Cushing's disease were excluded. Hydrocortisone substitution was started if peak cortisol levels were <550 nmol/L. The cortisol response was insufficient in 42(29%) and sufficient in 102 patients at the postoperative CRH-test. Thirteen of 42(30%) demonstrated a normal cortisol response during a second cortisol stimulation test. In 75 of the 102 patients with a sufficient response to CRH repeat testing revealed an insufficient cortisol response in 14 patients (14%). All but one had concomitant pituitary hormone deficits. There were no cases of adrenal crises during follow-up. Additional pituitary insufficiency was significantly more present (P < 0.001) in the group of patients with an abnormal response to CRH directly after surgery. In this study a substitution strategy of hydrocortisone guided by the postoperative cortisol response to CRH appeared safe and did not result in any case of adrenal crises. However, the early postoperative CRH-test does not reliably predict adrenal function after TS for pituitary adenomas in all patients and retesting is mandatory.

Background: The relationship between circulating ACTH levels and cortisol secretion in Cushing's disease is not precisely known., Hypothesis: Chronic ACTH hyperstimulation leads to decreased adrenal potency and is restored after normalization of ACTH secretion., Subjects: Subjects included 20 patients with Cushing's disease, eight patients in long-term remission, and 36 healthy controls., Outcomes: 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., Results: 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., Conclusion: 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.

Background: Recent analyses in small cohorts suggest that pituitary hormones exert time-varying (viz., initial and delayed) dynamic dose-responsive effects on target glands, wherein down-regulating dynamics are inferable on a time scale of single pulses., Hypothesis: Age, body mass index (BMI), and sex modulate the rapid potency-down-regulating dynamics of pulsatile pituitary ACTH-adrenal cortisol coupling overnight., Location: The study was conducted at a clinical translational research unit., Subjects: Subjects included healthy adults (48 women, 63 men; aged 18-77 yr; BMI 18-42 kg/m(2))., Outcomes: Outcomes included analytical dose-response estimates of endogenous ACTH efficacy, dynamic ACTH potency, and adrenal sensitivity from overnight 10-min ACTH-cortisol profiles., Results: Stepwise backward-elimination, multivariate-regression analysis revealed that in the combined cohorts (n = 111), age was associated with enhanced initial ACTH potency (R = 0.265, P = 0.005). Moreover, age and BMI jointly attenuated adrenal sensitivity (R = 0.334, P = 0.0017) and augmented down-regulated ACTH potency (R = 0.321 and P = 0.0028). Exploratory gender-segmented analyses showed that these outcomes might be explained by: (1) a negative effect of age in men on adrenal sensitivity (R = 0.270, P = 0.034) and (2) positive effects of age in men (R = 0.332, P = 0.0019) and BMI in women (R = 0.331, P = 0.024) on initial ACTH potency., Conclusions: In healthy adults, adrenal sensitivity to endogenous ACTH pulses, ACTH efficacy, and ACTH potency is associated with age, BMI, and gender. These findings may explain conflicting data in earlier literature and introduce the need to control all three of age, BMI, and sex in future studies of the stress-adaptive axis.

Context: The pituitary-adrenal axis in obesity and polycystic ovary syndrome (PCOS) is marked by increased urinary excretion of cortisol and its metabolites. It is not as yet clear whether the increased cortisol production in PCOS is related to obesity per se., Intervention and Methods: We investigated 15 obese PCOS women with a body mass index of 30-54 kg/m(2) and 15 healthy obese controls (body mass index 31-60 kg/m(2)) with a regular menstrual cycle. Patients and control women underwent 24-h blood sampling at 20-min intervals. Cortisol concentrations were measured with a sensitive assay. Data were analyzed with a new deconvolution program, approximate entropy, and cosinor regression., Outcome: Basal, pulsatile, and total cortisol production expressed per liter distribution volume, per square meter body surface, and as absolute amount per 24 h was similar in PCOS patients and matched healthy control women. In addition, the regularity of cortisol secretion and the diurnal properties were identical. Compared with 10 lean control women, mean cortisol production per liter distribution volume was similar in the three groups, but the total 24-h cortisol production was increased in obese control women and PCOS women., Conclusion: This study demonstrates equally increased cortisol production in PCOS women and obese healthy control women.

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.

Sex influences adrenal glucocorticoid responses to ACTH in experimental animals. Whether similar sex differences operate in humans is unknown. To test this notion, we estimated ACTH-cortisol dose-response properties analytically in 48 healthy adults (n = 22 women, n = 26 men), ages 18-77 yr, body mass index (BMI) 18-32 kg/m(2), previously studied at two medical centers. Plasma ACTH and cortisol concentrations were measured every 10 min for 24 h. The 145 sample pairs were used in each subject to estimate ACTH-cortisol drive via a logistic function. Statistical analyses revealed that 24-h cortisol secretion (>82% pulsatile) fell in men (r = -0.38, P = 0.028) and rose in women (r = +0.37, P = 0.045) with age (P = 0.01 sex effect). The mechanisms involved decreased ACTH efficacy with age in men (r = -0.35, P = 0.04), and increased ACTH efficacy with age in women (r = +0.42, P = 0.025) [P = 0.009 sex effect]. ACTH potency diminished with higher BMI in men (r = +0.38, P = 0.029) and in the cohort as a whole (r = 0.34, P = 0.0085). These outcomes demonstrate that sex, age, and BMI modulate selective properties of endogenous ACTH-cortisol drive in humans, thereby indicating the need to control these three major variables in experimental comparisons.

AutoDecon is a fully automatic, multiparameter deconvolution procedure that can be used to estimate various hormone secretion kinetics. We propose a strategy based on the application of the corrected Akaike's information criterion to select the optimal deconvolution model from a class of candidates generated by applying different combinations of initializing values. Using simulated cortisol time series, we show that, particularly in cases of diminished hormone half-life, this approach can yield estimates that are closer to the true underlying secretion kinetics compared with the commonly used approach based on a single set of initializing values. However, although we provide proof of principle, more extensive elaboration and validation of this approach are necessary.

Treatment with the atypical antipsychotic drug olanzapine is frequently associated with development of obesity and insulin resistance. Treatment-induced weight gain has been suggested to be the main contributing factor of diminished insulin sensitivity. This study evaluated the effects of short-term treatment with olanzapine on 12h plasma prolactin and cortisol concentrations in healthy men. The effects of two distinct olanzapine formulations were investigated; the oral standard tablets (OST) and the orally disintegrating tablets (ODT). Recent reports indicate that treatment with the ODT formulation may be less harmful in terms of weight gain than the OST. 12 healthy men (age: 25.1+/-5.5 y) received olanzapine OST (10mg QD, 8 days), olanzapine ODT (10mg QD, 8 days) or no intervention in a randomized cross-over design. On day 8, blood samples were taken every 10min between 0000 and 1200h for determination of cortisol and prolactin concentrations. Treatment with olanzapine OST and ODT similarly increased the 12h mean PRL concentrations and the secreted PRL mass. Both drugs similarly shifted the maximal PRL concentration approximately 3-4h backwards in time. Cortisol secretions rates were lower, but the timing of the cortisol acrophase did not change. Both drugs significantly elevated HOMA index for insulin resistance. In conclusion olanzapine OST and ODT equally elevated the prolactin concentration and significantly shifted its acrophase, thus dissociating PRL and cortisol, while both formulations induced similar insulin resistance as evidenced by the elevated HOMA-IR. Notably, these alterations occurred without a measurable effect on body adiposity.

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.

To evaluate the pathophysiology of altered cortisol secretion in patients with primary adrenal hypercortisolism, cortisol secretion was investigated in 12 patients, seven with a unilateral adenoma and five with ACTH-independent macronodular adrenal hyperplasia compared with age- and gender-matched controls and with patients with pituitary-dependent hypercortisolism. Pulsatile secretion was increased 2-fold (P = 0.04), attributable to increased event frequency (P = 0.002). All patients showed a significant diurnal rhythm with a delay in phase shift of 3 h (P = 0.01). Approximate entropy ratio, a feedback-sensitive measure, was increased compared with controls (P = 0.00003) but similar to that of pituitary-dependent hypercortisolism (P = 0.77), denoting loss of autoregulation. Cortisol burst-mass tended to be smaller in patients with ACTH-independent macronodular adrenal hyperplasia than in unilateral adenoma (P = 0.06). In conclusion, increased cortisol secretion in patients with primary adrenal Cushing's syndrome is caused by amplified pulsatile secretion via event frequency modulation. We speculate that partial preservation of secretory regularity and diurnal rhythmicity point to incomplete autonomy of these tumors.

According to current regulatory concepts, pulsatile ACTH concentrations (CON) stimulate time-lagged cortisol secretion rates (SEC) via an implicit CON-SEC dose-response relationship. The present analyses reconstruct nonlinear properties of this in vivo agonist-response interface noninvasively in order to investigate pulse-by-pulse coupling consistency and to obviate the need to infuse isotopes or exogenous effectors, which may disrupt pathway interactions. This approach required an ensemble strategy of 1) measuring ACTH and cortisol CON in plasma sampled every 10 min for 24 h in 32 healthy adults, and 2) estimating simultaneously a) variable-waveform ACTH and cortisol SEC bursts superimposed upon fixed basal SEC; b) biexponential kinetics of ACTH and cortisol disappearance; c) nonequilibrium exchange of cortisol among free and cortisol-binding globulin (CBG)- and albumin-bound moieties; d) two SEC-burst shapes demarcated by a statistically defined day/night boundary; e) feedforward efficacy, potency, and sensitivity; and f) stochastic variability in feedforward measures over time. Thereby, we estimate 1) ACTH SEC (microg.l(-1).day(-1)) of 0.27 +/- 0.04 basal and 0.87 +/- 0.07 pulsatile (means +/- SE); 2) cortisol SEC (micromol.l(-1).day(-1)) of 0.10 +/- 0.01 basal and 3.5 +/- 0.20 pulsatile; 3) free cortisol half-lives (min) of 1.8 +/- 0.20 (diffusion/advection) and 4.1 +/- 0.30 (elimination) and a half-life of total cortisol of 49 +/- 2.4 and of ACTH of 20 +/- 1.3; 4) ACTH potency (EC(50), ng/l) of 26 +/- 2.4, efficacy (nmol.l(-1).min(-1)) 10 +/- 1.8, and sensitivity (slope units) 0.65 +/- 0.09; 5) night/day augmentation of ACTH and cortisol SEC-burst mass by 2.1- and 1.7-fold (median); 6) abbreviation of the modal time to maximal ACTH and cortisol SEC rates by 4.4- and 4.3-fold, respectively, after a change point clock time of 0205 (median); 7) in vivo percentage distribution of cortisol as 6% free, 14% albumin bound, and 80% CBG bound with an absolute free cortisol CON (nmol/l) 11.5 +/- 0.54; and 8) significant (mean CV) stochastic variability in feedforward efficacy (140%), potency (38%), and sensitivity (56%) within the succession of paired ACTH/cortisol pulses of any given subject. In conclusion, the present composite formulation illustrates a platform for dissecting mechanisms of in vivo regulation of effector-response properties noninvasively in the corticotropic axis of the uninfused individual.

We assessed the value of postoperative plasma cortisol concentrations to predict cure and recurrence of Cushing's disease after transsphenoidal surgery (TS). Seventy-eight of 80 consecutive patients treated by TS for Cushing's disease were evaluated. TS cured 72% (n = 56) of the patients. Two weeks after surgery, patients with plasma cortisol levels below 138 nmol/liter (n = 50; three macroadenomas) and eight (27%) of 30 patients (nine macroadenomas) with cortisol greater than 138 nmol/liter were cured. Six (five with a macroadenoma) of these eight patients had cortisol values less than 50 nmol/liter 3 months after surgery. Therefore, the optimal cut-off value of cortisol predicting remission was 138 nmol/liter, measured 3 months after surgery (positive and negative predictive values 87 and 90%, respectively). Five patients (9%) had recurrent Cushing's disease during a median follow-up of 7 yr. Recurrence occurred in four of 24 (17%) patients with a follow-up of more than 10 yr. Therefore, cortisol levels above 138 nmol/liter, obtained 2 wk after TS, should be repeated, because they do not predict persistent Cushing's disease in 27% of those patients. Postoperative cortisol levels do not positively predict recurrence of disease during long-term follow-up of initially cured patients.

ACTH production in Cushing's disease is characterized by a markedly elevated rate of basal (nonpulsatile) secretion, an increased mass of ACTH released per burst and an unremarkable pulse frequency. In addition, the ACTH secretory process and that of GH and PRL exhibit profoundly disordered patterns. Whether some or all of these disturbances can be reversed or normalized by transsphenoidal microadenomectomy remains unknown. We therefore investigated the detailed dynamics of ACTH, GH, and PRL in eight patients (aged 38.9+/-4.2 yr) with pituitary-dependent Cushing's disease who were in long-term (8.2+/-1.7 yr) clinical remission following transsphenoidal surgery and eight controls matched for age, gender, and body mass index. To this end, blood was sampled at 10-min intervals for 24 h for the later assay of ACTH, cortisol, GH, and PRL. Secretory activity was quantitated by deconvolution methods, and the pattern orderliness (regularity) of hormone release was determined by the approximate entropy (ApEn) statistic. The joint synchrony of ACTH and cortisol secretion was monitored by the cognate bivariate statistic, cross-ApEn. Diurnal properties of the hormonal release were appraised by cosinor analysis. Based on deconvolution analysis, postsurgical patients exhibited a normal frequency, half-life, duration, and mass of ACTH and cortisol secretory bursts. Accordingly, the 24-h production rates of both ACTH (2.5+/-0.7 microg/L in patients vs. 2.9+/-0.7 microg/L in controls; P = 0.755) and cortisol (49+/-11 micromol/L in patients vs. 73+/-15 micromol/L in controls; P = 0.217) were normal also. The acrophase of the diurnal rhythm of ACTH (patients, 0817 h +/- 37 min; controls, 0850 h +/- 38 min; P = 0.629) and cortisol (patients, 1000 h +/- 24 min; controls, 0855 h +/- 30 min; P = 0.175) was also restored by surgery. ApEn values of ACTH (patients, 1.168 +/- 0.090; controls, 0.864+/-0.122; P = 0.133) and cross-ApEn of ACTH-cortisol (patients, 1.396+/-0.087; controls, 1.170+/-0.076; P = 0.140) secretion were both normal in this cohort, denoting restoration of the secretory process regularity. Cortisol ApEn was slightly higher in patients (patients, 1.034+/-0.084; controls, 0.831+/-0.038; P = 0.048). Both GH and PRL time series manifested full reconstitution of pulsatile, 24-h rhythmic, and entropic properties. In summary, clinically successful transsphenoidal microadenomectomy in adults with Cushing's disease can fully normalize virtually all quantitative features of regulated ACTH, cortisol, GH, and PRL secretion. Further studies will be needed to establish the consistency of these findings in larger cohorts of adults with Cushing's disease and in children with this disorder and to delineate the significance, if any, of a residual, minimally detectable disruption of orderly cortisol secretion in this patient population.

We examined serum concentration time-series for ACTH and cortisol in 20 patients with pituitary-dependent ACTH excess (Cushing's disease) and in 29 age- and gender-matched controls. For each subject, blood samples were obtained at 10-min intervals for 24 h. Joint ACTH-cortisol synchrony was quantified using the recently introduced cross-approximate entropy (cross-ApEn) statistic. In patients, cross-ApEn was greater than in controls (1.686 +/- 0.051 vs. 1.077 +/- 0.039, P = 3.45 x 10(-16), giving a sensitivity of 85%. In control subjects, but not in patients, cross-ApEn was correlated positively with age (r = 0.465, P = 0.011) There was no gender difference in cross-ApEn, nor a relationship between cross-ApEn and the 24-h ACTH and cortisol secretion, in patients or controls. In contrast, the maximal cross-correlation coefficient for the ACTH and cortisol series after detrending the series was 0.394 +/- 0.033 in controls and 0.297 +/- 0.034 in patients with considerable overlap of the subgroups, giving a sensitivity for this index of only 5%. In addition to previous findings of increased individual irregularity of ACTH and cortisol release in Cushing's disease, we can now also demonstrate greater joint asynchrony of the circulating concentrations of these hormones. Thus, Cushing's disease disrupts ensemble network secretory dynamics over individual hormone output. We conclude that, like GH-secreting pituitary and aldosterone-secreting adrenal tumors, ACTH-secreting pituitary tumors exhibit significant loss of orderly hormone release patterns. Moreover, Cushing's disease is marked further by deterioriation of bihormonal synchrony between ACTH and cortisol release, thus suggesting further erosion of within-axis feedback control.

We investigated the episodicity of 24-h ACTH and cortisol secretory profiles in 16 patients with Cushing's disease and 25 healthy matched controls, with a recently introduced scale- and model-independent regularity statistic, approximate entropy (ApEn). The mean (+/-S.E.M.) ApEn value for plasma ACTH concentrations in Cushing's disease was 1.3817 +/- 0.033, and in controls 0.8394 +/- 0.049 (P < 10(-10)); for plasma cortisol concentrations the values were 1.4575 +/- 0.052 and 0.8637 +/- 0.020 respectively (P < 10(-10)), implying greater irregularity of release for both hormones in Cushing's subjects. The calculated sensitivity and specificity of ApEn for ACTH profiles were 94% and 100% respectively. For cortisol the sensitivity and specificity were both 100%. ApEn was not correlated with sex, age, or the total 24-h secretion rate of ACTH and cortisol in patients and controls. The increased ApEn in patients with Cushing's disease points to an increased disorderliness of ACTH and cortisol secretion compared with healthy controls. In conjunction with the available literature, we hypothesize more generally that autonomous endocrine tumors may be typified by reduced regularity, orderliness, or synchrony of the time structure of hormone release.

We investigated 24-h ACTH and cortisol secretory profiles in 16 patients with Cushing's disease and 23 healthy controls. Blood samples were taken at 10-min intervals, and data were analyzed with a multiparameter deconvolution technique. The patients had the same number of ACTH pulses per 24 h as the controls (34 vs. 32/24 h) and similar plasma ACTH half-lives (17.4 +/- 0.7 vs. 19.3 +/- 0.5 min). The mass of ACTH secreted per pulse was increased, which was caused by an increased maximal secretion rate and prolonged secretion burst duration. The number of resolved cortisol pulses was less than that for ACTH, but higher in patients than in controls (24 vs. 17/24 h), with similar half-lives in both groups (57 +/- 2 vs. 59 +/- 4 min). The mass of cortisol secreted per pulse was higher in patients than in controls due to an increased maximal secretion rate attained within each burst. The mean total mass of 24-h cortisol production was 12.8 mg in controls (range, 6.7-20 mg) and 46 mg (range, 13.4-154) in patients. Basal secretion rates of ACTH and cortisol were increased 19-fold (ACTH) and 7-fold (cortisol) above control values in patients with Cushing's disease (P < 0.0002). The ratio of total 24-h cortisol and ACTH production (in mass units per L distribution volume) was 23 +/- 1.9 in controls and 11 +/- 2.3 in patients (P < 0.001). The secretory parameters for ACTH showed strong diurnal rhythms in control subjects, but were not significant in six patients. Diurnal rhythms for cortisol could be detected in only five patients. From these observations we conclude that cortisol and ACTH release in Cushing's disease is highly pulsatile, with the preservation of diurnal properties in only some patients. Markedly amplified total daily hormone secretion was attributed to a 19-fold (ACTH) and 7-fold (cortisol) higher basal secretion rate, increased secretory burst mass (ACTH and cortisol), and frequency (cortisol) in Cushing's disease. In addition, the apparent response of the adrenal gland to increased ACTH levels is diminished, suggesting decreased responsiveness of the adrenal glands.

We have investigated ACTH and cortisol secretion patterns in two groups of five healthy adult male and female subjects. Plasma samples were obtained at 10-min intervals for 24 h, and pulsatile hormone release was analyzed by a multiparameter deconvolution technique. ACTH secretion was greater in male than female subjects; the production rate per 24 h was 139 +/- 7 pmol/L distribution volume in males, and 89 +/- 11 pmol/L distribution volume in females (P = 0.007). Cortisol secretion did not differ significantly between sexes; in males, the 24-h secretion rate was 2807 +/- 239 nmol/L distribution volume, and in females, it was 2970 +/- 411 nmol/L distribution volume (P = NS). The number of ACTH secretory pulses per 24 h, as determined by deconvolution analysis, was 16.2 +/- 1.4 in males and 19.6 +/- 2.0 in females (P = NS). There were no sex differences in the number of cortisol pulses or the calculated half-lives of ACTH and cortisol. ACTH and cortisol pulses were significantly concordant at a cortisol lag time of 10 min, as demonstrated by probability analysis and cross-correlation with auto-regressive modeling. Based on a significantly different regression intercept of cortisol pulse height on ACTH pulse height in women than in men (P < 0.001) and a higher ratio of cortisol to ACTH production rates in women than in men (P = 0.013), we suggest that the female adrenal cortex is more responsive to ACTH than its male counterpart in terms of glucocorticoid production. Consequently, equivalent daily cortisol secretion rates are attained in men and women at the expense of greater ACTH release in men.