Esophageal Mycobacterium avium-intracellulare infection in a bone marrow transplant patient: Case report and literature review.

Mycobacterium avium-intracellulare complex (MAC) is the most common cause of nontuberculous mycobacterial (NTM) disease in humans. We report a case of esophageal MAC disease in a patient who had allogeneic bone marrow transplant for acute lymphoblastic leukemia. Although pulmonary MAC in immunocompromised host is not uncommon, there are only a few cases of NTM-associated esophageal mass reported. Our report and literature review highlight the importance of considering MAC in the differential diagnosis of dysphagia or odynophagia.

Motivations and methods for analyzing pulsatile hormone secretion.

Endocrine glands communicate with remote target cells via a mixture of continuous and intermittent signal exchange. Continuous signaling allows slowly varying control, whereas intermittency permits large rapid adjustments. The control systems that mediate such homeostatic corrections operate in a species-, gender-, age-, and context-selective fashion. Significant progress has been made in understanding mechanisms of adaptive interglandular signaling in vivo. Principal goals are to understand the physiological origins, significance, and mechanisms of pulsatile hormone secretion. Key analytical issues are: 1) to quantify the number, size, shape, and uniformity of pulses, nonpulsatile (basal) secretion, and elimination kinetics; 2) to evaluate regulation of the axis as a whole; and 3) to reconstruct dose-response interactions without disrupting hormone connections. This review will focus on the motivations driving and the methodologies used for such analyses.

Modeling the Nonlinear Time Dynamics of Multidimensional Hormonal Systems.

In most hormonal systems (as well as many physiological systems more generally), the chemical signals from the brain, which drive much of the dynamics, can not be observed in humans. By the time the molecules reach peripheral blood, they have been so diluted so as to not be assayable. It is not possible to invasively (surgically) measure these agents in the brain. This creates a difficult situation in terms of assessing whether or not the dynamics may have changed due to disease or aging. Moreover, most biological feedforward and feedback interactions occur after time delays, and the time delays need to be properly estimated. We address the following two questions: (1) Is it possible to devise a combination of clinical experiments by which, via exogenous inputs, the hormonal system can be perturbed to new steady-states in such a way that information about the unobserved components can be ascertained; and, (2) Can one devise methods to estimate (possibly, time-varying) time delays between components of a multidimensional nonlinear time series, which are more robust than traditional methods? We present methods for both questions, using the Stress (ACTH-cortisol) hormonal system as a prototype, but the approach is more broadly applicable.

Oscillations in joint synchrony of reproductive hormones in healthy men.

Negative-feedback (inhibitory) and positive-feedforward (stimulatory) processes regulate physiological systems. Whether such processes are themselves rhythmic is not known. Here, we apply cross-approximate entropy (cross-ApEn), a noninvasive measurement of joint (pairwise) signal synchrony, to inferentially assess hypothesized circadian and ultradian variations in feedback coupling. The data comprised simultaneous measurements of three pituitary and one peripheral hormone (LH, FSH, prolactin, and testosterone) in 12 healthy men each sampled every 10 min for 4 days (5,760 min). Ergodicity, due to the time series stationarity of the measurements over the 4 days, allows for effective estimation of parameters based upon the 12 subjects. Cross-ApEn changes were quantified via moving-window estimates applied to 4-day time series pairs. The resultant ordered windowed cross-ApEn series (in time) were subjected to power spectrum analysis. Rhythmicity was assessed against the null hypothesis of randomness using 1,000 simulated periodograms derived by shuffling the interpulse-interval hormone-concentration segments and redoing cross-ApEn windows and spectral analysis. By forward cross-ApEn analysis, paired LH-testosterone, LH-prolactin, and LH-FSH synchrony maintained dominant rhythms with periodicities of 18-22.5, 18, and 22.5 h, respectively (each P < 0.001). By reverse (feedback) cross-ApEn analysis, testosterone-LH, testosterone-prolactin, and testosterone-FSH synchrony cycles were 30, 18, and 30-45 h, respectively (each P ≤ 0.001). Significant 8- or 24-h rhythms were also detected in most linkages, and maximal bihormonal synchrony occurred consistently at ∼0400-0500. Collectively, these analyses demonstrate significant ultradian (<24 h), circadian (∼24 h), and infradian (>24 h) oscillations in pituitary-testis synchrony, wherein maximal biglandular coordination is strongly constrained to the early morning hours.

Differentiation of women with premenstrual dysphoric disorder, recurrent brief depression, and healthy controls by daily mood rating dynamics.

Enhanced statistical characterization of mood-rating data holds the potential to more precisely classify and sub-classify recurrent mood disorders like premenstrual dysphoric disorder (PMDD) and recurrent brief depressive disorder (RBD). We applied several complementary statistical methods to differentiate mood rating dynamics among women with PMDD, RBD, and normal controls (NC). We compared three subgroups of women: NC (n=8); PMDD (n=15); and RBD (n=9) on the basis of daily self-ratings of sadness, study lengths between 50 and 120 days. We analyzed mean levels; overall variability, SD; sequential irregularity, approximate entropy (ApEn); and a quantification of the extent of brief and staccato dynamics, denoted 'Spikiness'. For each of SD, irregularity (ApEn), and Spikiness, we showed highly significant subgroup differences, ANOVA0.001 for each statistic; additionally, many paired subgroup comparisons showed highly significant differences. In contrast, mean levels were indistinct among the subgroups. For SD, normal controls had much smaller levels than the other subgroups, with RBD intermediate. ApEn showed PMDD to be significantly more regular than the other subgroups. Spikiness showed NC and RBD data sets to be much more staccato than their PMDD counterparts, and appears to suitably characterize the defining feature of RBD dynamics. Compound criteria based on these statistical measures discriminated diagnostic subgroups with high sensitivity and specificity. Taken together, the statistical suite provides well-defined specifications of each subgroup. This can facilitate accurate diagnosis, and augment the prediction and evaluation of response to treatment. The statistical methodologies have broad and direct applicability to behavioral studies for many psychiatric disorders, and indeed to similar analyses of associated biological signals across multiple axes.

Oral hydrocortisone administration in children with classic 21-hydroxylase deficiency leads to more synchronous joint GH and cortisol secretion.

In humans, GH and cortisol are secreted in a pulsatile fashion and a mutual bidirectional interaction between the GH/IGF-I axis and hypothalamic-pituitary-adrenal axis has been established. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in the synthesis of glucocorticoids and often mineralocorticoids, and adrenal hyperandrogenism. Substitution therapy is given to prevent adrenal crises and to suppress the abnormal secretion of androgens and steroid precursors from the adrenal cortex. However, treatment with twice or three times daily oral hydrocortisone does not mimic physiological adrenal rhythms and may influence the activity of the GH/IGF-I axis. We investigated the pattern of GH and cortisol secretion and the synchrony of joint GH-cortisol secretory dynamics in 15 children with classic 21-hydroxylase deficiency (5 males and 10 females; median age 9.5 yr, range 6.1-11.0 yr) and 28 short normal children (23 males and 5 females; median age 7.7 yr, range 4.9-9.3 yr). All subjects were prepubertal. Serum GH and cortisol concentrations were determined at 20-min intervals for 24 h. The irregularity of GH and cortisol secretion was assessed using approximate entropy (ApEn), a scale- and model-independent statistic. The synchrony of joint GH-cortisol secretion was quantified using the cross-ApEn statistic. Cross-correlation analysis of GH and cortisol secretory patterns was computed at various time lags covering the 24-h period. Children with CAH had significantly lower mean 24-h serum cortisol concentrations (6.4 +/- 2.2 vs. 10.4 +/- 2.6 microg/dl, P < 0.001), ApEn (GH) (0.64 +/- 0.13 vs. 0.74 +/- 0.17, P = 0.04), ApEn (cortisol) (0.54 +/- 0.13 vs. 1.08 +/- 0.18, P < 0.001) and cross-ApEn values of paired GH-cortisol secretion (0.78 +/- 0.19 vs. 1.05 +/- 0.12, P < 0.001) than normal children. There was no difference in mean 24-h GH concentrations between the two groups (4.5 +/- 2.9 vs. 4.5 +/- 1.9 mU/liter). In children with CAH, a significant positive correlation between GH and cortisol was noted at lag time 0 min (r = 0.299, P < 0.01), peaking at 20 min (r = 0.406, P < 0.0001), whereas in normal children, a significant negative correlation between the two hormones was noted at lag time 0 min (r = -0.312, P < 0.01). The above findings suggest that children with classic CAH have a more regular pattern of GH secretion and a more synchronous joint GH-cortisol secretory dynamics than their normal counterparts. These differences reflect bidirectional interactions between the GH/IGF-I axis and hypothalamic-pituitary-adrenal axis in humans, and are likely to evolve as a result of the exogenous administration of hydrocortisone at fixed doses and at specific time intervals, which leads to a more regular pattern in circulating cortisol concentrations, independent of variations in CRH and ACTH concentrations.

Intracranial EEG evaluation of relationship within a resting state network.

OBJECTIVE: We tested if a relationship between distant parts of the default mode network (DMN), a resting state network defined by fMRI studies, can be observed with intracranial EEG recorded from patients with localization-related epilepsy. METHODS: Magnitude squared coherence, mutual information, cross-approximate entropy, and the coherence of the gamma power time-series were estimated, for one hour intracranial EEG recordings of background activity from 9 patients, to evaluate the relationship between two test areas which were within the DMN (anterior cingulate and orbital frontal, denoted as T1 and posterior cingulate and mesial parietal, denoted as T2), and one control area (denoted as C), which was outside the DMN. We tested if the relationship between T1 and T2 was stronger than the relationship between each of these areas and C. RESULTS: A low level of relationship was observed among the 3 areas tested. The relationships among T1, T2 and C did not demonstrate support for the DMN. CONCLUSIONS: This study suggests a lack of intracranial EEG support for the fMRI defined default mode network. SIGNIFICANCE: The results obtained underscore the considerable difference between electrophysiological and hemodynamic measurements of brain activity and possibly suggest a lack of neuronal involvement in the DMN.

Predicting response to leuprolide of women with premenstrual dysphoric disorder by daily mood rating dynamics.

Approximately 60-70 percent of women with premenstrual dysphoric disorder (PMDD) show symptomatic improvement in response to the GnRH agonist leuprolide acetate, which suppresses ovarian function. However, it has been very difficult to either predict or understand why some women respond, while others do not. We applied several complementary statistical methods to the dynamics of pre-treatment mood rating data to determine possible predictors of response for women with PMDD. We compared responders (n = 33) to nonresponders (n = 12) in clinical trials of leuprolide (three months in duration) as a treatment for PMDD, on the basis of pre-trial daily self-ratings of sadness, anxiety, and irritability. We analyzed both sequential irregularity (approximate entropy, ApEn) and a quantification of spikiness of these series, as well as a composite measure that equally weighted these two statistics. Both ApEn and Spikiness were significantly smaller for responders than nonresponders (P ≤ 0.005); the composite measure was smaller for responders compared with nonresponders (P ≤ 0.002) and discriminated between the subgroups with high sensitivity and specificity. In contrast, mean symptom levels were indistinct between the subgroups. Relatively regular and non-spiky pre-trial dynamics of mood ratings predict a positive response to leuprolide by women with PMDD with high probability, moreover based on typically less than 3 months of daily records. The statistical measures may have broad and direct applicability to behavioral studies for many psychiatric disorders, facilitating both accurate diagnosis and the prediction of response to treatment.

Regulation of complex pulsatile and rhythmic neuroendocrine systems: the male gonadal axis as a prototype.

Hormone-secreting glands communicate via intermittent (pulsatile or rhythmic) signal exchange. Signals act upon target glands via implicit (not directly observable) stimulatory and inhibitory dose-response functions. Time delays operate, since secreted hormones do not arrive at or act on responsive cells instantaneously. Neuroendocrine systems are unique examples, therefore, of intermittent time-delayed dose-dependent homeostatic ensembles. Investigating such ensembles thus requires estimating secretion from plasma concentrations, recognizing biological time-delays and reconstructing unobserved feedforward (agonist) and feedback (antagonist) dose-response interfaces as illustrated primarily for the GnRH-LH-T-axis, and secondarily for the corticotropic and somatotropic axes. In this manner, each neuroendocrine system is viewed as a whole, rather than the sum of individual parts.

Background intracranial EEG spectral changes with anti-epileptic drug taper.

OBJECTIVE: Previous studies have revealed a surprising decrease in spike counts and Teager energy between on- and off-AEDs states during intracranial EEG (icEEG) monitoring. Here, we expand the measures evaluated to icEEG power and frequency band power. METHODS: Two icEEG epochs, on- and off-AEDs, each 1h in duration, were studied for each of 21 unselected adult patients. Spike counts, Teager energy and total power were evaluated for each electrode contact. Power was also evaluated for delta (0-4Hz), theta (4-8Hz), alpha (8-13Hz), beta (13-25Hz), gamma (25-55Hz) and high (65-128Hz) frequency bands. RESULTS: A decrease in power accompanies AED taper and the previously reported decrease in spike counts and Teager energy. The decrease in power was underpinned by a spatially widespread and broadband decrease in power in delta through gamma frequency bands with maximum decrease in the lowest frequency bands. An increase in high-frequency power was observed in some patients. CONCLUSIONS: There is a decrease in spike counts, Teager energy and power from on- to off-AEDs state during intracranial monitoring. The decrease in power is spatially widespread and broadband including power in the delta through gamma frequency bands. SIGNIFICANCE: The decrease in cortical activity with AED taper suggests that seizure generation during intracranial monitoring may not be mediated solely by poorly regulated cortical excitation.

Localization-related epilepsy exhibits significant connectivity away from the seizure-onset area.

In localization-related epilepsy, seizures are presumed to arise from a discrete cortical area. The control of seizures by epilepsy surgery can be poor, however, even when there has been complete resection of the area identified by standard clinical procedures to give rise to seizures. We used a coherence-based measure of functional connectivity to test for network effects within and outside the seizure-onset area. Connectivity was evaluated from the background intracranial electroencephalogram of six unselected patients. We show significant nonzero connectivity not only for the seizure-onset area but also several centimeters from it, for example, for the beta-frequency band (P<10(-5)), suggesting a nonlocal character to this disorder.

Basal, pulsatile, entropic (patterned), and spiky (staccato-like) properties of ACTH secretion: impact of age, gender, and body mass index.

BACKGROUND: Age, gender, and BMI determine ultradian modes of LH and GH secretion, viz., pulsatile, basal, pattern-defined regularity [approximate entropy (ApEn)] and spikiness (sharp, brief excursions). Whether the same determinants apply to ACTH secretion is not known. SETTING: The study was conducted at a tertiary medical center. SUBJECTS: We studied normal women (n = 22) and men (n = 26) [ages, 23-77 yr; body mass index (BMI), 21-32 kg/m(2)]. METHODS: Volunteers underwent 10-min blood sampling to create 24-h ACTH concentration profiles. OUTCOMES: Dynamic measures of ACTH secretion were studied. RESULTS: Mean ACTH concentrations (R(2) = 0.15; P = 0.006) and both pulsatile (R(2) = 0.12; P = 0.018) and basal (nonpulsatile) (R(2) = 0.16; P = 0.005) ACTH secretion correlated directly with BMI (n = 48). Men had greater basal (P = 0.047), pulsatile (P = 0.031), and total (P = 0.010) 24-h ACTH secretion than women, including when total secretion was normalized for BMI (P = 0.019). In men, both ACTH-cortisol feedforward and cortisol-ACTH feedback asynchrony (cross-ApEn) increased with age (R(2) = 0.20 and 0.22; P = 0.021 and 0.018). ACTH spikiness rose with age (P = 0.046), principally in women. Irregularity of cortisol secretion (ApEn) increased with age (n = 48; P = 0.010), especially in men. In both sexes, percentage pulsatile ACTH secretion predicted 24-h mean cortisol concentrations (R(2) = 0.14; P = 0.009). CONCLUSION: Valid comparisons of ultradian ACTH dynamics will require cohorts matched for age, gender, and BMI, conditions hitherto not satisfied in most physiological studies of this axis.

A decrease in EEG energy accompanies anti-epileptic drug taper during intracranial monitoring.

OBJECTIVE: During intracranial EEG (icEEG) monitoring the likelihood of observing a seizure is increased by tapering anti-epileptic drugs (AEDs). Presumably AED taper results in an increase in cortical excitation which in turn promotes seizure emergence. We measured change in signal energy of icEEGs in response to AED taper to quantify changes in excitation which accompany the increased propensity for seizures. METHODS: Twelve consecutive adult patients who completed intracranial monitoring were studied. Two icEEG epochs from before and after AED taper, each 1h in duration, during wake, matched by time-of-day and removed from seizures were selected for each patient. Teager energy, a frequency weighted measure of signal energy, was estimated for both the seizure onset region as well as all other brain areas monitored. RESULTS: Considerable changes in Teager energy, evaluated at a 1-h time-resolution, occur during intracranial monitoring. The most dominant trend is a decrease to lower values than those when the patient is on AEDs. A decrease of 35% was observed for both all the brain areas monitored and the seizure onset region. CONCLUSIONS: A decrease in signal energy occurs during intracranial EEG monitoring, possibly accompanying AED taper. If the decrease is due to AED taper this would suggest that AEDs prevent seizures in ways other than reduction of cortical excitation and seizure generation may be influenced by factors other than poorly regulated cortical excitation.

A noninvasive measure of negative-feedback strength, approximate entropy, unmasks strong diurnal variations in the regularity of LH secretion.

The secretion of anterior-pituitary hormones is subject to negative feedback. Whether negative feedback evolves dynamically over 24 h is not known. Conventional experimental paradigms to test this concept may induce artifacts due to nonphysiological feedback. These limitations might be overcome by a noninvasive methodology to quantify negative feedback continuously over 24 h without disrupting the axis. The present study exploits a recently validated model-free regularity statistic, approximate entropy (ApEn), which monitors feedback changes with high sensitivity and specificity (both >90%; Pincus SM, Hartman ML, Roelfsema F, Thorner MO, Veldhuis JD. Am J Physiol Endocrinol Metab 273: E948-E957, 1999). A time-incremented moving window of ApEn was applied to LH time series obtained by intensive (10-min) blood sampling for four consecutive days (577 successive measurements) in each of eight healthy men. Analyses unveiled marked 24-h variations in ApEn with daily maxima (lowest feedback) at 1100 +/- 1.7 h (mean +/- SE) and minima (highest feedback) at 0430 +/- 1.9 h. The mean difference between maximal and minimal 24-h LH ApEn was 0.348 +/- 0.018, which differed by P < 0.001 from all three of randomly shuffled versions of the same LH time series, simulated pulsatile data and assay noise. Analyses artificially limited to 24-h rather than 96-h data yielded reproducibility coefficients of 3.7-9.0% for ApEn maxima and minima. In conclusion, a feedback-sensitive regularity statistic unmasks strong and consistent 24-h rhythmicity of the orderliness of unperturbed pituitary-hormone secretion. These outcomes suggest that ApEn may have general utility in probing dynamic mechanisms mediating feedback in other endocrine systems.

Approximate entropy as a measure of irregularity for psychiatric serial metrics.

OBJECTIVES: The quantification of subtle patterns in sequential data, and their changes, has considerable potential utility throughout psychiatry, including the analyses of mood ratings, heart rate, respiratory, and electroencephalographic recordings. METHODS: Approximate entropy (ApEn), a relatively recently developed statistic quantifying serial irregularity, has been applied in numerous studies throughout mathematics and other fields of study, especially biology. RESULTS: We discussed applications of ApEn, both extant and potential, of most relevance to psychiatrists. We provided a mechanistic interpretation of lowered ApEn values, and discusses the relationship between ApEn and other (both classical and complexity) measures of serial dynamics. We also briefly discussed cross-ApEn, a thematically similar quantification of two-variable asynchrony that can aid in uncovering subtle disruptions in complicated network dynamics. CONCLUSIONS: ApEn and cross-ApEn have significant potential to consequentially enhance present statistical methodologies of analysis of psychiatric data, in both clinical and in research settings.

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.

Testosterone (T) secretion declines in the aging male, albeit for unknown reasons. From an ensemble perspective, repeated incremental signaling among gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and T is required to maintain physiological androgen availability. Pattern-regularity statistics, such as univariate approximate entropy (ApEn) and bivariate cross-ApEn, provide specific and sensitive model-free measurement of altered multi-pathway control. The present study exploits partial muting of one pathway (GnRH drive) to appraise adaptive regulation of LH and T secretion in young and aging individuals. Analyses comprised 100 paired 18-h LH and T concentration time series obtained in 25 healthy men ages 20-72 yr each administered placebo and three graded doses of a specific GnRH-receptor antagonist. Graded blockade of GnRH drive increased the individual regularity of LH and T secretion and the synchrony of LH-T feedforward and T-LH feedback in the cohort as a whole (P<0.001 for each). However, age markedly attenuated ganirelix-induced enhancement of univariate T orderliness and bivariate LH-T feedback and T-LH feedback synchrony (P

The length of perimenopausal menstrual cycles increases later and to a greater degree than previously reported.

OBJECTIVE: To demonstrate that the perimenopausal increase in menstrual cycle length presented by Treloar et al. was biased by misidentified menopause dates, mean values classified by calendar year, and exclusion of menstrual cycles straddling two calendar years; and to use the revised data to investigate women's experiences of longer perimenopausal cycles. DESIGN: Secondary analysis of prospectively collected menstrual cycle data. SETTING: Center for Population and Health, Georgetown University. PATIENT(S): One hundred twenty white, college-educated, US women in the Tremin Research Program on Women's Health. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Mean cycle length and time spent in >40-day cycles, by year before menopause. RESULT(S): Mean estimates for each of the 4 years before menopause were 30.48, 35.02, 45.15, and 80.22 days, respectively, compared with the original analysis: 33.60, 43.91, 55.87, and 54.58 days. In the year before menopause, the majority of women spent >or=75% of their time in cycles >40 days long. CONCLUSION(S): Treloar's estimates of mean cycle length were biased. Long cycles occurred throughout perimenopause, but the largest increase in mean cycle length did not occur until the final year before menopause. New estimates of the time spent in cycles >40 days may be useful clinically as well as epidemiologically for assessing menopausal onset and symptomatology.

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.

Analysis of bidirectional pattern synchrony of concentration-secretion pairs: implementation in the human testicular and adrenal axes.

The hypothalamo-pituitary-testicular and hypothalamo-pituitary-adrenal axes are prototypical coupled neuroendocrine systems. In the present study, we contrasted in vivo linkages within and between these two axes using methods without linearity assumptions. We examined 11 young (21-31 yr) and 8 older (62-74 yr) men who underwent frequent (every 2.5 min) blood sampling overnight for paired measurement of LH and testosterone and 35 adults (17 women and 18 men; 26-77 yr old) who underwent adrenocorticotropic hormone (ACTH) and cortisol measurements every 10 min for 24 h. To mirror physiological interactions, hormone secretion was first deconvolved from serial concentrations with a waveform-independent biexponential elimination model. Feedforward synchrony, feedback synchrony, and the difference in feedforward-feedback synchrony were quantified by the cross-approximate entropy (X-ApEn) statistic. These were applied in a forward (LH concentration template, examining pattern recurrence in testosterone secretion), reverse (testosterone concentration template, examining pattern recurrence in LH secretion), and differential (forward minus reverse) manner, respectively. Analogous concentration-secretion X-ApEn estimates were calculated from ACTH-cortisol pairs. X-ApEn, a scale- and model-independent measure of pattern reproducibility, disclosed 1) greater testosterone-LH feedback coordination than LH-testosterone feedforward synchrony in healthy men and significant and symmetric erosion of both feedforward and feedback linkages with aging; 2) more synchronous ACTH concentration-dependent feedforward than feedback drive of cortisol secretion, independent of gender and age; and 3) enhanced detection of bidirectional physiological regulation by in vivo pairwise concentration-secretion compared with concentration-concentration analyses. The linking of relevant biological input to output signals and vice versa should be useful in the dissection of the reciprocal control of neuroendocrine systems or even in the analysis of other nonendocrine networks.