HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 289/1/E160    most recent 00007.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Liu, P. Y. Articles by Veldhuis, J. D. Search for Related Content PubMed PubMed Citation Articles by Liu, P. Y. Articles by Veldhuis, J. D.

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

¹Division of Endocrinology, Department of Internal Medicine, Endocrine Research Unit and General Clinical Research Center, Mayo Clinic, Mayo Medical and Graduate Schools of Medicine, Rochester, Minnesota; ²990 Moose Hill Road, Guilford, Connecticut; ³Department of Statistics, University of Virginia, Charlottesville, Virginia; and ⁴Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands

Submitted 7 January 2005 ; accepted in final form 20 February 2005

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
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.

adrenocorticotropin; regulation; statistic; cross-approximate entropy; neuroendocrine stress

The stress-responsive adrenocorticotropic (ACTH) axis influences amino acid, glucose, and lipid metabolism, immunologic reactivity, bone mass, muscle strength, and neuronal function. Regulation of the corticotropic axis proceeds via hypothalamic secretion of peptidyl secretagogues (1), which stimulate exocytotic release and de novo synthesis of ACTH by pituitary corticotropes (1, 3). ACTH concentrations drive secretion of adrenal glucocorticoids (3), which in turn inhibit the output of central secretagogues and ACTH (4, 8, 21). Accordingly, physiological or pathological states could modify any given feedforward or feedback pathway either primarily (by way of local interruption) or secondarily (due to expected network-like adaptations to the interruption).

Signals generated by neuroendocrine systems pose a unique analytic challenge. For example, neurochemical and hormonal signals direct target cell secretion via nonlinear dose-response interfaces, maintain variable input-output time lags, and manifest marked (>30-fold) fluctuations in signal size; in addition, signals are confounded by associated stochastic variabilities (6–8, 18). These properties have motivated the development of lag time-, scale-, and model-independent strategies, which complement the information gained by conventional linear techniques, such as cross-correlation and cross-spectral analyses (discussed in Ref. 15). In this regard, in an effort to discriminate adaptations in feedforward and feedback control, we recently proposed pair-wise synchrony analysis using the cross-approximate entropy (X-ApEn) statistic applied in a directionally specific fashion (12). X-ApEn is a lag time-invariant, scale-independent, and model-free measure of joint-signal coordination in coupled time series (14–16). Evaluation of forward and reverse X-ApEn has disclosed system-specific differences in two-hormone synchrony of feedforward vs. feedback in the normal human corticotropic and gonadotropic axes (12). What remains unknown is whether directional X-ApEn analyses would be able to 1) identify interruption of a primary pathway and 2) quantify adaptive responses by reciprocal pathways under experimentally controlled conditions.

To address these issues, our study implements directionally defined (forward and reverse) X-ApEn as a means to quantify changes in the pairwise synchrony of ACTH-cortisol and cortisol-ACTH signaling (see METHODS). Our paradigmatic models included normal and elevated ACTH feedforward (input) to cortisol secretion (output) and normal, elevated, or reduced cortisol feedback (input) on ACTH secretion (output). We hypothesized that forward and reverse X-ApEn analyses would unmask direction- and pathway-specific controls in this prototypical neuroendocrine axis.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Clinical sampling protocol to assess normal and autonomously elevated ACTH and cortisol secretion. Thirty-five normal subjects (17 women and 18 men) ages 26–77 yr (mean 44 yr) and 21 patients (14 women and 7 men) ages 18–74 yr (mean 38 yr) with Cushing disease were enrolled after providing written, informed consent, as approved by the local ethics committee. Normal young women were studied in the early follicular phase of the menstrual cycle. The diagnosis of Cushing disease was confirmed in all cases 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, suppression of plasma cortisol concentration by 190 nmol/l or more during a 7-h intravenous infusion of dexamethasone at a dose of 1 mg/h, positive immunostaining for ACTH of the pituitary adenoma, and clinical cortisol dependency for several months after selective removal of the adenoma. Corresponding secretion data, but not forward and reverse X-ApEn, were described in these patients (17). The control series is utilized here for comparison with those in the Cushing disease group.

Blood samples were withdrawn every 10 min for 24 h starting at 0900. Subjects were allowed to ambulate within the study unit but were not allowed to exercise vigorously. Lights were turned off between 2200 and 2400, depending on individual sleep habits.

Clinical sampling protocol to assess the effect of cortisol depletion induced by metyrapone. Nine normal subjects (4 women and 5 men) aged 24–62 yr (median 45 yr) were studied after placebo and metyrapone administration on 2 consecutive days, as reported earlier (11). X-ApEn analyses have not been performed previously. Entry criteria included normal body weight (for height), conventional work and sleeping patterns with no recent transmeridian travel, no recent dieting or weight gain, no intercurrent psychosocial stress, no medication, hormone, or glucocorticoid use, no drug or alcohol abuse, no neuropsychiatric illness, and no acute or chronic systemic disease. A complete medical history, physical examination, and structured psychiatric interview screening for substance abuse and disorders of mood, eating, behavior, personality, and/or psychosis showed unremarkable results. Biochemical tests of hematological, renal, hepatic, metabolic, and endocrine function were normal. Pregnancy tests and urinary drug screening were negative.

The sampling protocol comprised blood withdrawal (0.75 ml) every 10 min for 48 h beginning at midnight. Volunteers arrived at 1900 and rested quietly until sampling began. At midnight, volunteers were given oral placebo capsules every 2 h for 24 h (baseline, day 1); metyrapone was then administered every 2 h for an additional 24 h (experimental day 2). The dose was 1,000 mg orally every 2 h for six doses, followed by 500 mg every 2 h for six additional doses; doses were administered with milk and crackers to improve tolerability.

Assays. ACTH samples were collected on ice in chilled EDTA-containing siliconized glass tubes, and cortisol samples were collected in heparinized tubes. Blood was centrifuged at 4°C, and the plasma separated within 30 min and then frozen at –20°C (Cushing protocol) or –70°C (metyrapone protocol) for later analysis. ACTH concentrations were assayed in duplicate by immunoradiometric assay (Nichols Laboratories, San Juan Capistrano, CA) (17). The sensitivity of the ACTH assay is 3.0 ng/l. There is <0.1% cross-reactivity with -MSH, LH FSH, TSH, growth hormone, and prolactin. The intra- and interassay coefficients of variation were <6% and <7.5%, respectively. Plasma concentrations of total cortisol were measured by solid-phase RIAs (from Sorin Biomedica, Milan, Italy in the Cushing's study; and from Diagnostic Products, Los Angeles, CA in the metyrapone study). Assay sensitivity was 1.5 µg/dl, and the interassay coefficient of variation was <8%. All samples from a given subject were assayed together to eliminate interassay variance.

Calculation of secretion. Sample ACTH and cortisol secretion rates were estimated from measured hormone concentrations using previously validated waveform-independent deconvolution analysis (19). The procedure assumes known biexponential elimination kinetics, as given earlier for both hormones (17).

X-ApEn statistics. The univariate ApEn statistic was developed to quantify the degree of irregularity or disorderliness of a time series (13). Technically, ApEn quantifies the summed logarithmic likelihood that templates (of length m) of patterns in the data that are similar (within r) remain similar (within the same tolerance r) on next incremental comparison, as formally defined elsewhere (14). ApEn is a nonnegative number, which is an ensemble estimate of relative process randomness, wherein larger ApEn values denote greater irregularity.

X-ApEn is a bivariate analog of ApEn and quantifies joint pattern synchrony between two separate but linked time series after standardization (z-score transformation of the data) (12, 15, 16). In the present analyses, we calculated X-ApEn, assuming r = 20% of the SD of the individual time-series and m = 1, and hence use the designation X-ApEn (1, 20%). This parameter set affords sensitive, valid, and statistically well replicated ApEn and X-ApEn metrics for assessing hormone time series of this length (15).

The interpretation of X-ApEn as implemented here depends on whether pattern recurrence is assessed against the downstream or upstream sequence. By way of convention, we computed forward X-ApEn using serial ACTH concentrations as the template to assess pattern reproducibility in cortisol secretion rates and calculated reverse X-ApEn by employing successive cortisol concentrations as the template to evaluate pattern recurrence in ACTH secretion rates. Note that, for physiological reasons, the foregoing schema of pairing relates the concentration of an input signal to the secretion rate of the output signal. In addition, for any given input-output pair, differential X-ApEn was defined as forward minus reverse X-ApEn. The difference term monitors changes in the symmetry of feedforward and feedback adaptations.

Statistics. A one- and two-sample t-test with Bonferroni adjustment was utilized to compare X-ApEn values in volunteers given placebo vs. metyrapone and in normal subjects vs. patients with Cushing disease, respectively. The significance of differential X-ApEn values was evaluated by a one-sample rank-sum test against a null hypothesis of a zero difference. Statistical tests were two-sided with P < 0.025 considered significant, given that both forward and reverse X-ApEn were assessed. Data are means ± SE. Analyses were performed using SAS version 9.1 (SAS Institute).

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Figure 1 illustrates paired time series obtained in 3 subjects. The profiles highlight feedforward (ACTH concentration cortisol secretion) and feedback (cortisol concentration ACTH secretion) linkages in a normal adult, a patient with autonomous tumoral ACTH secretion (Cushing disease), and a healthy volunteer under normal (placebo) vs. low cortisol feedback (metyrapone administration). Individual forward and reverse X-ApEn values are stated in each panel. Higher X-ApEn values denote reduced two-hormone synchrony and vice versa (see METHODS).

View larger version (68K): [in this window] [in a new window]   Fig. 1. Time series illustrating paired ACTH concentrations and cortisol secretion rates (feedforward, left) and paired cortisol concentrations and ACTH secretion rates (feedback, right) in the 3 conditions studied, that is, a normal adult (top), a patient with Cushing disease (middle), and a healthy volunteer given metyrapone to block cortisol synthesis (bottom). The forward (left) or reverse (right) cross-approximate entropy (X-ApEn) values are shown in each panel. Higher X-ApEn values denote greater two-hormone asynchrony. Data were obtained by sampling blood every 10 min for 24 h followed by deconvolution analysis to generate secretion series. and dashed curves, Secretion plots. and solid curves, Concentration profiles.

View larger version (16K): [in this window] [in a new window]   Fig. 2. Forward (top) and reverse (bottom) X-ApEn quantification of joint synchrony of ACTH and cortisol concentration-secretion (con-sec) pairs in normal adults (n = 35) and in patients with Cushing disease (n = 21). P values reflect unpaired contrasts.

View larger version (23K): [in this window] [in a new window]   Fig. 3. Top: differences between X-ApEn of ACTH-cortisol concentration-secretion and cortisol-ACTH concentration-secretion time series (forward – reverse X-ApEn) in normal subjects (n = 35) and in patients with Cushing disease (n = 21). P value beside each difference tests the null hypothesis of a zero difference between feedforward and feedback X-ApEn values. Overall P value was >0.05 for comparing normal and Cushing's X-ApEn difference values. Bottom: relationship between reverse and forward X-ApEn values in the same 2 cohorts with line of identity.

View larger version (21K): [in this window] [in a new window]   Fig. 4. Forward (top) and reverse (bottom) X-ApEn quantification of two-signal coordination of ACTH-cortisol and cortisol-ACTH concentration-secretion time series in 9 normal adults administered placebo or metyrapone. P values reflect paired comparisons.

View larger version (23K): [in this window] [in a new window]   Fig. 5. X-ApEn differences (top) and relation between forward and reverse X-ApEn values (bottom) in the same subjects. See Fig. 3 for format of data presentation.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

Cushing disease is defined by autonomous ACTH secretion by a pituitary adenoma, which is sparingly suppressible by negative feedback. We previously observed that feedforward coupling between ACTH and cortisol concentrations is disrupted in Cushing disease (17). The accompanying data extend this inference by applying X-ApEn analyses to 1) the physiologically more pertinent feedforward pair, ACTH concentrations, and cortisol secretion and 2) the reciprocal feedback linkage between cortisol concentrations and ACTH secretion, thereby documenting marked loss of inhibitory coupling as well (Fig. 2). Combined and commensurate disruption of feedforward and feedback linkages would define prima facie secretory autonomy, as inferred in clinical studies of this disease (5, 9).

Metyrapone is a potent inhibitor of the final step in cortisol biosynthesis, thereby depleting systemic glucocorticoid availability and decreasing feedback signal strength (2). The low cortisol milieu induced by this drug decreased the joint synchrony of ACTH concentrations and cortisol secretion rates, which fulfills the biological prediction of feedforward impairment during steroidogenic blockade (20). Low cortisol feedback concomitantly enhanced feedback-dependent synchrony of cortisol concentrations and ACTH secretion, thereby illustrating divergent adaptations in feedforward and feedback coupling. Although the order of metyrapone and placebo administration was not randomized, a sequence effect is highly unlikely to explain the >30-fold elevation of ACTH secretion and >67% suppression of cortisol concentrations induced by this drug (11). The continuous low rate of cortisol secretion enforced by steroidogenic inhibition may be relevant in augmenting the joint regularity of cortisol and ACTH release, in view of the recent observation that feedback imposed by continuous intravenous infusion of testosterone in acutely hypoandrogenemic men heightens the regularity of LH secretion more than pulsatile delivery of the same amount of testosterone (22). More generally, the hypocortisolemic model establishes that directional X-ApEn provides a suitable strategy to identify pathway-defined and directionally specific adaptations noninvasively in an interlinked hormonal system.

Several technical considerations are pertinent to interpreting the present outcomes. First, synchrony between input (effector concentration) and output (secretion response) patterns was assessed in a scale-invariant and lag-independent manner, thus obviating bias otherwise introduced by hormone concentration differences imposed by the disease or the intervention or by inconsistent effector-response time delays (15). Second, X-ApEn of paired signal synchrony confers model-free quantification of complex dynamics, thus complementing parametric model-based analyses (8, 11). Third, feedforward/feedback symmetry of two-signal coupling was evaluated on a within-subject basis to optimize statistical power, given anticipated biological variability among individuals. Finally, fourth, separate forward and reverse X-ApEn measures allow appraisal of directionally distinct pathways, and calculated differences between forward and reverse X-ApEn permit assessment of the symmetry of feedforward and feedback adaptations.

We conclude that quantification of the synchrony of directionally paired ACTH-cortisol and cortisol-ACTH signals can probe pathway-selective disruption or enhancement of feedback or feedforward coupling in an interlinked endocrine axis. Validation is based on delineating reduced synchrony of 1) cortisol-ACTH feedback in patients with autonomous (glucocorticoid-nonsuppressible) tumoral ACTH secretion and 2) ACTH-cortisol feedforward in normal subjects during pharmacological inhibition of cortisol secretion. Specificity of inference was achieved by documenting directionally opposite adaptations in the synchrony of ACTH-cortisol feedforward and cortisol-ACTH feedback in response to induced hypocortisolemia. The collective outcomes support the regulatory concept that disruption of any single connection within an ensemble system evokes complementary adaptations in other pathways.

The accompanying analyses highlight insights gained by directionally defined, lag-invariant, model-free, and scale-independent statistical assessments of the synchrony of biologically coupled signals that mediate feedforward and feedback control in an interlinked system. The pattern-sensitive probabilistic nature of X-ApEn complements classical linear metrics, such as cross-correlation or cross-spectral analyses, as well as nonlinear model-based parametric assessments of coordinated signal exchange. An extension of the concept of direction- and pathway-defined X-ApEn might entail combining model-free and model-specific approaches to dissect more subtle mechanisms of physiological regulation. A long-term goal would be to identify the primary pathways involved in physiological adaptations and quantitate secondary responses in a noninvasive manner.

	GRANTS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
P. Y. Liu was supported by fellowships from the National Health and Medical Research Council of Australia (Grant 262025) and the Royal Australasian College of Physicians. Studies were supported in part by National Center for Research Resources Grant M01 RR-00585 to the General Clinical Research Center of the Mayo Clinic and Foundation; National Institutes of Health Grants RO1 DK-60717, K01 AG-19164, and AG-23133; and National Sciences Foundation Interdisciplinary Grant DMS-0107680.

	ACKNOWLEDGMENTS

 
This focused report necessarily omitted many primary references because of editorial constraints.

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. D. Veldhuis, Division of Endocrinology, Dept. of Internal Medicine, Endocrine Research Unit and General Clinical Research Center, Mayo Clinic, Mayo Medical and Graduate Schools of Medicine, 200 First St. Southwest, Rochester, MN 55905 (e-mail: Veldhuis.Johannes{at}mayo.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 

1. Alexander SL, Irvine CH, and Donald RA. Short-term secretion patterns of corticotropin-releasing hormone, arginine vasopressin and ACTH as shown by intensive sampling of pituitary venous blood from horses. Neuroendocrinology 60: 225–236, 1994.[ISI][Medline]
2. Berneis K, Staub JJ, Gessler A, Meier C, Girard J, and Muller B. Combined stimulation of adrenocorticotropin and compound-S by single dose metyrapone test as an outpatient procedure to assess hypothalamic-pituitary-adrenal function. J Clin Endocrinol Metab 87: 5470–5475, 2002.[Abstract/Free Full Text]
3. Dempsher DP, Gann DS, and Phair RD. A mechanistic model of ACTH-stimulated cortisol secretion. Am J Physiol Regul Integr Comp Physiol 246: R587–R596, 1984.[Abstract/Free Full Text]
4. Dorin RL, Ferries LM, Roberts B, Qualls CW, Veldhuis JD, and Lisansky EJ. Assessment of stimulated and spontaneous adrenocorticotropin secretory dynamics identifies distinct components of cortisol feedback inhibition in healthy humans. J Clin Endocrinol Metab 81: 3883–3891, 1996.[Abstract/Free Full Text]
5. Fliser D, Veldhuis JD, Dikow R, Schmidt-Gayk H, and Ritz E. Effects of ACE inhibition on pulsatile renin and aldosterone secretion and their synchrony. Hypertension 32: 929–934, 1998.[Abstract/Free Full Text]
6. Giustina A and Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 19: 717–797, 1998.[Abstract/Free Full Text]
7. Keenan DM, Alexander SL, Irvine CHG, Clarke IJ, Canny BJ, Scott CJ, Tilbrook AJ, Turner AI, and Veldhuis JD. Reconstruction of in vivo time-evolving neuroendocrine dose-response properties unveils admixed deterministic and stochastic elements in interglandular signaling. Proc Natl Acad Sci USA 101: 6740–6745, 2004.[Abstract/Free Full Text]
8. Keenan DM, Licinio J, and Veldhuis JD. A feedback-controlled ensemble model of the stress-responsive hypothalamo-pituitary-adrenal axis. Proc Natl Acad Sci USA 98: 4028–4033, 2001.[Abstract/Free Full Text]
9. Keenan DM, Roelfsema F, and Veldhuis JD. Endogenous ACTH concentration-dependent drive of pulsatile cortisol secretion in the human. Am J Physiol Endocrinol Metab 287: E652–E661, 2004.[Abstract/Free Full Text]
10. Keenan DM and Veldhuis JD. A biomathematical model of time-delayed feedback in the human male hypothalamic-pituitary-Leydig cell axis. Am J Physiol Endocrinol Metab 275: E157–E176, 1998.[Abstract/Free Full Text]
11. Keenan DM and Veldhuis JD. Cortisol feedback state governs adrenocorticotropin secretory-burst shape, frequency and mass in a dual-waveform construct: time-of-day dependent regulation. Am J Physiol Regul Integr Comp Physiol 285: R950–R961, 2003.[Abstract/Free Full Text]
12. Liu PY, Pincus SM, Keenan DM, Roelfsema F, and Veldhuis JD. Analysis of bidirectional pattern synchrony of concentration-secretion pairs: implementation in the human testicular and adrenal axes. Am J Physiol Regul Integr Comp Physiol 288: R440–R446, 2005.[Abstract/Free Full Text]
13. Pincus SM. Approximate entropy as a measure of system complexity. Proc Natl Acad Sci USA 88: 2297–2301, 1991.[Abstract/Free Full Text]
14. Pincus SM and Kalman RE. Not all (possibly) "random" sequences are created equal. Proc Natl Acad Sci USA 94: 3513–3518, 1997.[Abstract/Free Full Text]
15. Pincus SM, Mulligan T, Iranmanesh A, Gheorghiu S, Godschalk M, and Veldhuis JD. Older males secrete luteinizing hormone and testosterone more irregularly, and jointly more asynchronously, than younger males. Proc Natl Acad Sci USA 93: 14100–14105, 1996.[Abstract/Free Full Text]
16. Pincus SM and Singer BH. Randomness and degrees of irregularity. Proc Natl Acad Sci USA 93: 2083–2088, 1996.[Abstract/Free Full Text]
17. Roelfsema F, Pincus SM, and Veldhuis JD. Patients with Cushing's disease secrete adrenocorticotropin and cortisol jointly more asynchronously than healthy subjects. J Clin Endocrinol Metab 83: 688–692, 1998.[Abstract/Free Full Text]
18. Urban RJ, Evans WS, Rogol AD, Kaiser DL, Johnson ML, and Veldhuis JD. Contemporary aspects of discrete peak detection algorithms. I. The paradigm of the luteinizing hormone pulse signal in men. Endocr Rev 9: 3–37, 1988.[ISI][Medline]
19. Veldhuis JD, Moorman J, and Johnson ML. Deconvolution analysis of neuroendocrine data: waveform-specific and waveform-independent methods and applications. Methods Neurosci 20: 279–325, 1994.
20. Veldhuis JD, Straume M, Iranmanesh A, Mulligan T, Jaffe CA, Barkan A, Johnson ML, and Pincus SM. Secretory process regularity monitors neuroendocrine feedback and feedforward signaling strength in humans. Am J Physiol Regul Integr Comp Physiol 280: R721–R729, 2001.[Abstract/Free Full Text]
21. Widmaier EP and Dallman MF. The effects of corticotropin-releasing factor on adrenocorticotropin secretion from perifused pituitaries in vitro: rapid inhibition by glucocorticoids. Endocrinology 115: 2368–2374, 1984.[Abstract]
22. Zwart A, Iranmanesh A, and Veldhuis JD. Disparate serum free testosterone concentrations and degrees of hypothalamo-pituitary-LH suppression are achieved by continuous vs. pulsatile intravenous androgen replacement in men: a clinical experimental model of ketoconazole-induced reversible hypoandrogenemia with controlled testosterone add-back. J Clin Endocrinol Metab 82: 2062–2069, 1997.[Abstract/Free Full Text]

This article has been cited by other articles:

				H. G. Klemcke, J. L. Vallet, and R. K. Christenson Lack of effect of metyrapone and exogenous cortisol on early porcine conceptus development Exp Physiol, May 1, 2006; 91(3): 521 - 530. [Abstract] [Full Text] [PDF]

				J. J. Meier, L. L. Kjems, J. D. Veldhuis, P. Lefebvre, and P. C. Butler Postprandial suppression of glucagon secretion depends on intact pulsatile insulin secretion: further evidence for the intraislet insulin hypothesis. Diabetes, April 1, 2006; 55(4): 1051 - 1056. [Abstract] [Full Text] [PDF]

				P. Y. Liu, S. M. Pincus, P. Y. Takahashi, P. D. Roebuck, A. Iranmanesh, D. M. Keenan, and J. D. Veldhuis Aging attenuates both the regularity and joint synchrony of LH and testosterone secretion in normal men: analyses via a model of graded GnRH receptor blockade Am J Physiol Endocrinol Metab, January 1, 2006; 290(1): E34 - E41. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 289/1/E160    most recent 00007.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Liu, P. Y. Articles by Veldhuis, J. D. Search for Related Content PubMed PubMed Citation Articles by Liu, P. Y. Articles by Veldhuis, J. D.