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Patients with Cushing’s Disease Secrete Adrenocorticotropin and Cortisol Jointly More Asynchronously than Healthy Subjects

Department of Endocrinology (F.R), Leiden University Medical Center, Leiden 2333AA, The Netherlands; Guilford, Connecticut (S.M.P.); Department of Medicine, National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 22908

Address correspondence and requests for reprints to: Dr. F. Roelfsema, Department of Endocrinology, Leiden University Medical Center, Albinusdreef 2, 2333AA, Leiden, The Netherlands. E-mail: roelfsema{at}rullf2.MedFac.LeidenUniv.nl

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
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.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
CLASSICALLY, endocrine diseases are thought to be the result of excessive or decreased secretion of a particular hormone. More recently, abnormalities have often been characterized by changes in pulsatility or irregularity of secretory dynamics apart from mean level changes. In Cushing’s disease, we recently demonstrated that the secretion of ACTH, and also that of cortisol, is highly irregular, as quantified by the Approximate Entropy (ApEn) statistic (1, 2, 3, 4). Disorganized hormone secretion has also been described in other endocrine pathophysiologies such as GH secretion in acromegaly and aldosterone secretion in aldosterone-secreting adrenal adenomas, and also for insulin secretion in relatives of patients with noninsulin dependent diabetes mellitus (5, 6, 7). Although considerable insight has been obtained recently in associating irregular hormone secretion with various pathophysiological states by applying ApEn analysis to individual hormone data series, we wish now to gain insight into the network aspects operating operating within an axis, beyond observations taking one hormone at a time.

A recently introduced measure of asynchrony or conditional irregularity, cross-ApEn (8) affords such a statistical capability applied to a pair of (hormone) signals. The usefulness of cross-ApEn for evaluating coupled endocrine systems was recently demonstrated in an analysis of LH-testosterone (T) synchrony in cohorts of younger vs. older males (9). In particular, the older males exhibited markedly more jointly asynchronous LH-T dynamics than did the younger group, leading us to hypothesize that, analogous to one-dimensional signal analysis, regularity and synchronicity generally correspond more to (normal) physiology, whereas greater irregularity (apparent process randomness) and increased (two-variable) asynchronicity correspond to pathophysiology, aging, and other variants of network disruption. Below, we investigate the emerging hypothesis that ACTH-cortisol bihormonal secretory dynamics are more asynchronous in Cushing’s disease than in controls. Validating this theme would both offer further evidence of this broadly-stated paradigm and provide some initial insights into explicit network manifestations of secretory tumors beyond the vivid one-variable increases in irregularity seen for ACTH and cortisol, individually (4).

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

Fourteen female and six male patients (mean age 37 yr, range 17–74 yr) were studied. In all patients the diagnosis of Cushing’s disease was established by elevated 24-h urinary excretion of free cortisol, subnormal or absent overnight suppression of plasma cortisol by 1 mg oral dexamethasone, absent or subnormal suppression of urinary cortisol excretion during an oral 2-day dexamethasone test (low-dose Liddle test), suppression of plasma cortisol concentration by 190 nmol/L or more during a 7-h iv infusion with dexamethasone at a dose of 1 mg/h (10), positive immunostaining for ACTH of the pituitary adenoma, and clinical cortisol dependency for several months after selective removal of the adenoma. Four patients had undergone previous transsphenoidal surgery. Two other patients had been treated many years earlier by unilateral adrenalectomy and pituitary radiation, which was the standard therapy for Cushing’s disease in our institute before the application of transsphenoidal surgery in the early 1970’s. All these six subjects had clinical and biochemical relapse during follow-up studies.

The patients were hospitalized the evening before the sampling studies. On the following morning, an indwelling iv cannula was inserted in a large vein of the forearm, and blood samples were withdrawn at 10-min intervals starting at 0900 h and for the next 24 h. A slow iv infusion of 0.9% NaCl and heparin (1 U/mL) was used to keep the line open. The subjects were free to move around, but not to sleep during daytime. Meals were served at 0800, 1230, and 1730 h. Lights were turned off between 2200–2400 h, depending on the sleeping habits of the patient. As controls, 12 healthy male and 17 healthy female volunteers underwent the same plasma sampling study. Their mean age was 42 yr, range 30–63 yr (NS vs. patients).

Plasma samples for ACTH were collected on ice in chilled ethylenediamine tetraacetate-containing siliconized glass tubes, and samples for cortisol were collected in heparinized tubes. The samples were centrifuged at 4 C, and within 30 min the plasma was separated, frozen, and stored at -20 C until the assay was performed. All samples from any subject were run in duplicate in the same assay (see below).

Informed consent was obtained from all subjects and patients, and the study was approved by the ethical committee of the Leiden University Hospital.

Assays

Plasma ACTH concentrations were measured in duplicate by immunoradiometric assay, using reagents obtained from the Nichols’ Institute (San Juan Capristrano, CA). In our hands the detection limit of this assay was 3.0 ng/L. The intra- and interassay precision varied from 2.8–7.5%. The cross-reactivity of this assay with MSH, LH, FSH, TSH, GH, and PRL was less than 0.1%. Plasma cortisol concentrations were measured by RIA (Sorin Biomedica, Milan, Italy). The detection limit of this assay was 25 nmol/L. The intra- and interassay precision varied from 2–4%.

Cross-approximate entropy (cross-ApEn)

To quantify asynchrony (conditional irregularity), we use cross-ApEn, as introduced in ref 8, definition 5. As noted there, cross-ApEn can be employed to compare sequences from two distinct yet intertwined variables in a network, herein applied to the joint ACTH-cortisol time-series. Larger cross-ApEn values indicate greater joint signal asynchrony. The precise mathematical definition is thematically similar to that for ApEn:

Let u = (u(1), u(2), ... . u(N)) and v = (v(1), v(2), ... . v(N)) be two N-length sequences. Fix input parameters m and r. Form vector sequences x(I) = (u(I), u(I+1),... . u(I+m-1)) and y(j) = (v(j), v(j+1),... . v(j+m-1)) from u and v, respectively. For each IN-m+1, set C_i ^m(r)(v u) = (number of j N-m+1 such that d[x(I), y(j)] r)/(N-m+1), where d[x(I), y(j)] = max_{k = 1,2... . . m}( u(I+k-1)-v(j+k-1) ), i.e. the maximum difference in their respective scalar components. The C_i ^m(r)’s measure within a tolerance r the regularity, or frequency, of (v-) patterns similar to a given (u-) pattern of window length m. Then define ^m(r)(v u) as the average value of ln ^m(r)(v u), and finally define cross-ApEn (m, r, N)(v u) = ^m(r)(v u)-^m+1(r)(v u). For this study, we applied cross-ApEn with m = 1, and r = 0.2 to standardized ACTH ( = u) and cortisol ( = v) time-series data, i.e. for each subject we applied cross-ApEn to the {u^*(I),v^*(j)}series, where u^*(I) = (u(I)-mean u)/SD u and v^*(j) = (v(j)-mean v)/SD v. This standardization, in conjunction with the choices of m and r, ensures appropriate replicability properties for cross-ApEn for the data lengths studied (1, 2, 3, 8).

Deconvolution analysis

Multiple parameter deconvolution was used to estimate various specific measures of hormone secretion and half-life from all plasma hormone concentrations and their dose-dependent intrasample variances considered simultaneously (11). In normal subjects basal secretion constituted only a small part of the 24-h cortisol and ACTH production. In most patients, however, basal release forms a substantial part of total production. The latter is the sum of basal production and pulsatile production, which were estimated as described (12, 13). For the present study only the total production rates are reported. Detailed data on the deconvolution parameters of ACTH and cortisol secretion in Cushing’s disease were published recently (14). Here, we relate these data to cross-ApEn calculations.

Statistical analysis

Data are given as the mean ± SEM, unless otherwise mentioned. Statistical comparison of data in patients and controls (or male vs. female) was performed with the two-tailed Student’s t-test for unpaired data. Linear regression analysis and ANOVA were applied where appropriate, and cross-correlation analysis both on raw data and after prewhitening of the data series. Significant parametric differences were corroborated by non-parametric tests (Mann-Whitney U test, Wilcoxon signed rank test). Calculations were made with SPSS Windows version 7.0 and with Systat (SPSS Inc., Chicago, ILL). P < 0.05 was considered significant.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Cross-ApEn(1, 20%) was 1.686 ± 0.051 in patients and 1.077 ± 0.039 in controls (P = 3.45 x 10^-16). In Fig. 1, the plasma ACTH and cortisol profiles of a female control subject and a patient with Cushing’s disease are depicted with the calculated cross-ApEn for both subjects. We determined a significant positive correlation between cross-ApEn(1, 20%) and age in controls (r = 0.465, P = 0.011), but not in patients (r = 0.067, P = 0.779). From the 95% confidence interval, shown in Fig. 2, it is clear that only 3 out of 20 patients had a cross-ApEn value within the normal age-related range, giving a sensitivity of 85%. Cross-ApEn did not correlate with the 24-h ACTH and cortisol production, estimated with the deconvolution analysis. The classical cross-correlation function (CCF) was significant for all ACTH-cortisol concentration data series, and the maximal r value obtained in controls was 0.74 ± 0.04, and 0.56 ± 0.05 in patients (P = 0.007). The mean time lag at maximal ACTH and cortisol correlation was 7.9 min in controls, and 9.5 min in patients (NS). Because the raw data series exhibited a high degree of autocorrelation, we removed these by differencing the raw data series with a lag of 10 min. After this procedure, the cross correlation decreased to 0.39 ± 0.03 in controls and to 0.30 ± 0.03 in patients (P = 0.046). No significant regression of the CCF on age was present. Notably, the CCF obtained after detrending the data series resulted in an almost complete overlap of the data of patients and controls (see Table 1). In addition, we also measured copulsatility with a specific hypergeometric probability-density program (15), after identifying significant peaks in the data series with Cluster analysis (2x1 cluster size, t-statistics = 2.0 for up- and downstrokes, ref. 16). In a time window of 10 min, patients had 149 coincident peaks, while the expected number by chance would be 97 ± 7.9 (mean ± SD). In the control group, the respective numbers were 197 and 114 ± 8.9. In terms of z-score, in controls the coupling was 9.3 SD above expectation, and in patients 6.6 SD.

View larger version (24K): [in this window] [in a new window]   Figure 1. Plasma concentrations of ACTH (dotted line) and cortisol (continuous line) in a female patient with Cushing’s disease (upper panel) and a control subject (lower panel), each sampled at 10-min intervals for 24 h.

View larger version (20K): [in this window] [in a new window]   Figure 2. Relationship between cross-ApEn(1, 20%) and age in patients with Cushing’s disease () and control subjects (). There is a pronounced statistical separation between controls and patients, with only three patients having a cross-ApEn value within the control subject limits. Hence, the sensitivity of cross-ApEn is 85%. The regression line and the 95% confidence lines are shown. The correlation coefficient was 0.465 (P = 0.011) for controls, but not significant in the patients, indicating increasing asynchrony with advancing age in the healthy cohort only.

We then explored whether ApEn or cross-ApEn exhibits diurnal variation in patients and controls. To this end the 24-h period was divided into three equal parts of eight hours, starting at 0900 h in the morning. ApEn(1, 20%) for ACTH in patients was 1.085 ± 0.036, 1.124 ± 0.038 and, 1.087 ± 0.027 in the respective 8-h blocks (ANOVA P = 0.264), and the respective means for the controls were 0.937 ± 0.054, 0.948 ± 0.041, and 0.826 ± 0.031 (ANOVA P = 0.076). ApEn(1, 20%) for cortisol in patients was 1.083 ± 0.037, 1.173 ± 0.035, and 1.168 ± 0.032 (ANOVA P = 0.016), and for controls 0.923 ± 0.036, 0.897 ± 0.033 and 0.821 ± 0.035(ANOVA P = 0.135). The ANOVA’s for the mean concentrations of cortisol and ACTH during the 8-h blocks were statistically insignificant for the patients (P = 0.171 and 0.948, respectively) and highly significant for controls (P < 0.0005, individual data not given).

There was an overall significant difference of cross-ApEn between patients and controls (P < 0.005). Gender had no statistical influence on the results. In controls, the ANOVA was significant (P = 0.036), manifesting a clear decrease in cross-ApEn during the third period, i.e. during the night and early morning, from 1.224 ± 0.059 and 1.262 ± 0.051 in the first two 8-h blocks to 1.086 ± 0.036. In patients, we also found a significant diurnal variation (P = 0.002), showing lower cross-ApEn values during the first part of the period, i.e. daytime. The values determined were 1.361 ± 0.048, 1.485 ± 0.054, and 1.505 ± 0.034, respectively. This diversity of cross-ApEn is clearly demonstrated in Fig 3.

View larger version (13K): [in this window] [in a new window]   Figure 3. Cross-ApEn (1, 20%) in patients () and controls (•). The 24-h period was divided into three periods of 8 h each. Both patients and controls exhibited a diurnal variation in cross-ApEn, although with a clearly different pattern. Note that within each time period the degree of ACTH-cortisol asynchrony in patients is greater (higher cross-ApEn) than in control subjects.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

An independent technique for investigating the coupling between ACTH and cortisol pulses was the application of copulsatility analysis (15). Although we found for both patients and controls a highly significant coincidence of pulses within the biologically relevant time window, the coupling tightness was much higher in controls than in patients, adding independent evidence for the asynchrony of the pituitary-adrenal axis in Cushing’s disease. At this point we want to stress that copulsatility does not bear on subordinate dynamics, in contrast to both ApEn and cross-ApEn, which algorithmically do so by comparisons over all pieces of time series, and not only peaks or nadirs. Thus, if primary ACTH pulses remained "answered" by an adrenal cortisol pulse, with the latter’s subordinate features altered, cross-ApEn would detect this, while the copulsatility analysis would not, even apart from considerations as to the quality of the copulsatility algorithm and its statistical implementation.

The utility of cross-ApEn is also evidenced when the analyses are compared with those of the cross-correlation function (CCF) of the ACTH and cortisol time sequences. As noted above, there is a large control-patient CCF value subgroup overlap, upon standard removal of (spurious) autocorrelations prior to the CCF analyses. As discussed in ref. 9, this observation is not surprising because, as indicated there, the autocorrelation function and CCF are typically most effective in linear systems, e.g. ARMA models, oftentimes less so for other classes of models. Nonetheless, the present results reinforce the complementarity and nonredundancy of cross-ApEn, copulsatility, and CCF, as techniques to potentially detect changes in bivariate data behavior.

In our normal subjects, we found an age-related increase of cross-ApEn pointing to a decrease in the synchrony of ACTH and cortisol release with advancing age. A similar finding has been reported for the LH-testosterone system in healthy males and was attributed to a decreased feedback signal strength or to diminished GnRH-LH-testosterone system responsiveness to feedforward and feedback signal control (9). However, there is a primary mechanistic difference between the results of the present analyses and those of the LH-T study. Specifically, in that study, each of LH and T exhibited a significant increase in serial irregularity with increasing age, in addition to the joint signal change in asynchrony. In contrast, within the control group of the present study, there was an insignificant correlation between age and ApEn of cortisol (r = 0.207, P = 0.450) and a borderline correlation between age and ApEn of ACTH (r = 0.409, P = 0.046). This suggests the new inference that aging affects network or ensemble aspects of the ACTH-cortisol system, i.e. conduits, links, and/or global control mechanisms, more so than it does individual glandular secretory activity. Further studies will be necessary to pinpoint the precise physiologic changes that elicit the presently seen statistical contrasts.

Interestingly, we also found a clear, nonsex-dependent diurnal variation of cross-ApEn, with the lowest values (highest synchrony) during the night period, i.e. when the ACTH-cortisol system comes to its maximal activity during sleep. At this portion of the 24-h cycle, the normal system shows tight coupling in contrast with the Cushing’s disease patients. The physiological pathways by which this coupling is accomplished are not clear at this time, as the nodal components of the regulatory system did not exhibit evident diurnal properties. The observation as to the diurnal variation in cross-ApEn is only valid if the application of 48 data points for the calculation of cross-ApEn is justified and when the circulating hormone concentrations are well above the detection limit in the 3 time segments. Monte Carlo simulation experiments show only slight degradation of the typical theoretical limits of (cross-)ApEn replicability for 48 data points (1, 2, 3, 8). The application of 48 data points to determine diurnal changes is therefore justified, and if anything, the uncertainty in the application of 8-h blocks would tend to diminish differences. Furthermore, in all 3 time segments, both for patients and controls, ACTH and cortisol concentrations were detectable well above the detection limits of the assays, so that assay noise could not have influenced the calculation of ApEn and cross-ApEn.

Finally, although we have shown increased cross-ApEn of ACTH-cortisol secretion in Cushing’s disease, it is not proven at this point whether the increased cross-ApEn is caused by Cushing’s disease or by the increased ACTH-cortisol secretion. Additional studies in other states of hypercortisolism, such as untreated congenital adrenal hyperplasia, and the cortisol resistance syndrome will ultimately be required to provide an answer to this question. Nonetheless, the present study further shows that cross-ApEn values can be dissociated from secretion levels per se, as increased cross-ApEn is found with advancing age without increased secretion and with no relation existed between cortisol and ACTH secretion rates and cross-ApEn values in Cushing’s disease.

Received April 11, 1997.

Revised July 30, 1997.

Revised October 7, 1997.

Accepted October 22, 1997.

	References

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				J. D. Veldhuis, M. Straume, A. Iranmanesh, T. Mulligan, C. Jaffe, A. Barkan, M. L. Johnson, and S. Pincus Secretory process regularity monitors neuroendocrine feedback and feedforward signaling strength in humans Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2001; 280(3): R721 - R729. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, S. M. Pincus, R. Mitamura, K. Yano, N. Suzuki, Y. Ito, Y. Makita, and A. Okuno Developmentally Delimited Emergence of More Orderly Luteinizing Hormone and Testosterone Secretion during Late Prepuberty in Boys J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 80 - 89. [Abstract] [Full Text]

				M. Bergendahl, A. Iranmanesh, C. Pastor, W. S. Evans, and J. D. Veldhuis Homeostatic Joint Amplification of Pulsatile and 24-Hour Rhythmic Cortisol Secretion by Fasting Stress in Midluteal Phase Women: Concurrent Disruption of Cortisol-Growth Hormone, Cortisol-Luteinizing Hormone, and Cortisol-Leptin Synchrony J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4028 - 4035. [Abstract] [Full Text]

				R. G. Veldman, M. Frölich, S. M. Pincus, J. D. Veldhuis, and F. Roelfsema Apparently Complete Restoration of Normal Daily Adrenocorticotropin, Cortisol, Growth Hormone, and Prolactin Secretory Dynamics in Adults with Cushing's Disease after Clinically Successful Transsphenoidal Adenomectomy J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4039 - 4046. [Abstract] [Full Text]

				M. Bergendahl, A. Iranmanesh, T. Mulligan, and J. D. Veldhuis Impact of Age on Cortisol Secretory Dynamics Basally and as Driven by Nutrient-Withdrawal Stress J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2203 - 2214. [Abstract] [Full Text]

				J. D. Veldhuis, A. Iranmanesh, M. Godschalk, and T. Mulligan Older Men Manifest Multifold Synchrony Disruption of Reproductive Neurohormone Outflow J. Clin. Endocrinol. Metab., April 1, 2000; 85(4): 1477 - 1486. [Abstract] [Full Text]

				M. Bergendahl, A. Iranmanesh, W. S. Evans, and J. D. Veldhuis Short-Term Fasting Selectively Suppresses Leptin Pulse Mass and 24-Hour Rhythmic Leptin Release in Healthy Midluteal Phase Women without Disturbing Leptin Pulse Frequency or Its Entropy Control (Pattern Orderliness) J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 207 - 213. [Abstract] [Full Text]

				M. Bergendahl, W. S. Evans, C. Pastor, A. Patel, A. Iranmanesh, and J. D. Veldhuis Short-Term Fasting Suppresses Leptin and (Conversely) Activates Disorderly Growth Hormone Secretion in Midluteal Phase Women--A Clinical Research Center Study J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 883 - 894. [Abstract] [Full Text]

				A. Giustina and J. D. Veldhuis Pathophysiology of the Neuroregulation of Growth Hormone Secretion in Experimental Animals and the Human Endocr. Rev., December 1, 1998; 19(6): 717 - 797. [Abstract] [Full Text]

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