Pathophysiology of hypercortisolism in depression: pituitary and adrenal responses to low glucocorticoid feedback.

OBJECTIVE: To test three theories of hypercortisolemia in depression-hypothalamic overdrive, impaired glucocorticoid feedback, or autonomous cortisol production. METHOD: We applied an overnight low-cortisol feedback strategy by administering metyrapone to hypercortisolemic depressed in-patients and control subjects. RESULTS: Under metyrapone, the increases of plasma adrenocorticotropic hormone (ACTH) concentrations and of basal and pulsatile ACTH secretion were not exaggerated in hypercortisolemic depressed patients compared with control subjects. ACTH approximate entropy (ApEn) did not differ at baseline or under metyrapone. Thus, neither hypothalamic overdrive nor irregular ACTH secretion was seen. We did not detect impaired cortisol feedback: the ACTH response was not reduced, and ApEn measures that are sensitive to feedback changes were comparable in both groups. Metyrapone disrupted cortisol secretory regularity in depressed and control subjects. On the baseline day, basal cortisol secretion was significantly increased and was highly irregular (high ApEn), and ACTH-cortisol cross-ApEn was markedly elevated in high-cortisol patients. CONCLUSION: Classical feed-forward overdrive and impaired feedback theories of hypercortisolemia in depression were not supported. Depressive hypercortisolemia may result from alternative pathophysiological mechanisms involving irregular basal hypersecretion of cortisol, associated with adrenal enlargement, possibly through splanchnic sympathetic activation of the adrenal cortex.

Mechanisms of ensemble failure of the male gonadal axis in aging.

The systemic availability of testosterone (Te) falls by 35-50% after the sixth decade of life in healthy men. Intercurrent illness, trauma, surgery, stress, weight loss, diverse medications and institutionalization reduce Te concentrations further. Impoverishment of anabolic drive probably contributes to physical frailty and diminished quality of life in older individuals. However, the fundamental mechanisms that mediate hypoandrogenemia in the aging male remain unknown. Recent clinical experiments offer new clues to the mechanistic bases of Te depletion in older men. In particular, the following attributes mark aging-related Te withdrawal: (a) high-frequency and low-amplitude LH pulses; (b) disorderly LH-release patterns, consistent with feedback disruption; (c) normal or heightened LH secretion following single or repeated GnRH stimuli; (d) reduced Te secretory-burst mass with normal basal Te secretion; and (e) impaired Leydig-cell Te production in response to secreted LH pulses (stimulated by flutamide, tamoxifen, GnRH or anastrozole) and infused (recombinant human) LH pulses. The foregoing interconnected findings allow us to frame the integrative postulate that androgen deprivation in the older male reflects multisite failure in the GnRH-LH-testosterone axis. The most proximate locus of impairment is not yet known.

Noninvasive in vivo investigative probes of adaptive mechanisms of neuroendocrine regulation: the paradigm of the hypothalamo-pituitary-gonadal axis in the aging male.

Intermittent signal exchange serves to encode repeated incremental adjustments among central-neural centers and the ensemble of glands comprising any given axis. Interglandular communication proceeds dynamically via pulsatile and basal modes of hormone release, deterministic (dose-responsive) interfaces, and apparently stochastic (randomly varying) processes. Physiological investigations of the time-dependent control of neurohormone secretion and action depend upon valid reconstruction of such interactive signaling. Recent technical and experimental advances afford new and fundamental insights into such composite mechanisms that maintain precise homeostasis in health, and show susceptibility to disruption in disease. Underlying concepts are becoming more readily understandable intuitively without full rehearsal of detailed analytical and statistical facets that undergird computer-assisted methods. Accordingly, the present overview highlights core precepts that guide the implementation of sensitive, specific and utilitarian technologies to quantitate neuroendocrine adaptations in pathophysiology. The aging male gonadal axis provides a well studied paradigmatic platform to illustrate the formulation and implementation of analytical strategies in diverse systems.

Disruption of the hypothalamic luteinizing hormone pulsing mechanism in aging men.

The incremental nature of neuroendocrine aging suggests that subtle system dysregulation may precede overt axis failure. The present analyses unmask threefold disruption of pulsatile gonadotropin-releasing hormone (GnRH)-luteinizing hormone (LH) secretion in the aging male. First, by way of random effects-based deconvolution analysis, we document an elevated daily GnRH-LH pulse frequency in healthy older men [namely, mean (+/-SE) 23 +/- 1 (older) vs. 15 +/- 1 (young) LH secretory bursts/24 h, P < 0.001] and lower mean LH pulse mass [3.73 +/- 0.58 (older) vs. 5.46 +/- 0.66 (young) IU/l, P = 0.038]. However, total LH secretion rates and two-compartment LH elimination kinetics were comparable in the two age cohorts. Second, using the approximate entropy statistic, we show an equivalently random order-dependent succession of LH interpulse-interval lengths in young and older men, but a marked age-related deterioration of the ad seriatim regularity of LH pulse mass series in older individuals (P = 0.0057). Third, by modeling GnRH pulse-generator output as a Weibull renewal process (generalized Gamma density) to emulate loosely coupled GnRH neuronal oscillators, we identify an age-related reduction in the frequency-independent and order-independent variability of GnRH-LH interpulse-interval sets (P = 0.08). These findings indicate that the GnRH-LH pulsing mechanism in healthy older men maintains an increased mean frequency and lower amplitude of bursting activity, a reduced uniformity of serial LH pulse-mass values, and an impaired variability among interpulse-interval lengths. Thereby, the foregoing order-dependent and order-independent alterations in GnRH-LH signal generation in the aging human suggest a general framework for exploring subtle disruption of time-sensitive regulation of other neurointegrative systems.

Hypothesis testing of the aging male gonadal axis via a biomathematical construct.

Neuroendocrine axes are feedback- and feedforward-coupled dynamic ensembles. Disruption of selected pathways in such networklike organizations may explicate loss of orderly hormonal output as observed in aging. To test this notion more explicitly, we implemented an earlier computer-assisted biomathematical model of the interlinked male hypothalamo [gonadotropin-releasing hormone (GnRH)]-pituitary [luteinizing hormone, (LH)]-testicular [Leydig cell testosterone (Te)] axis (Am J Physiol Endocrinol Metab Physiol 275: E157--E176, 1988; Keenan D., W. Sun, and J. D. Veldhuis, SIAM J Appl Math 61: 934--965, 2000). Thereby, we appraise mechanistic hypotheses for more disorderly LH and Te secretion in aging men. We compare model predictions with monitored abnormalities in the older male, namely, irregular patterns of individual and synchronous LH and Te release, reduced 24-h rhythmic Te output, and variably elevated LH secretion. Among the mechanisms examined, the most parsimonious aging hypothesis would entail impaired LH feedforward on Te without or with attenuated Te feedback on GnRH/LH secretion. This investigative strategy should aid in exploring new postulates of disrupted feedback networks in pathophysiology.

A feedback-controlled ensemble model of the stress-responsive hypothalamo-pituitary-adrenal axis.

The present work develops and implements a biomathematical statement of how reciprocal connectivity drives stress-adaptive homeostasis in the corticotropic (hypothalamo-pituitary-adrenal) axis. In initial analyses with this interactive construct, we test six specific a priori hypotheses of mechanisms linking circadian (24-h) rhythmicity to pulsatile secretory output. This formulation offers a dynamic framework for later statistical estimation of unobserved in vivo neurohormone secretion and within-axis, dose-responsive interfaces in health and disease. Explication of the core dynamics of the stress-responsive corticotropic axis based on secure physiological precepts should help to unveil new biomedical hypotheses of stressor-specific system failure.

Explicating hypergonadotropism in postmenopausal women: a statistical model.

Neurohormone secretion is viewed here as a variable (unknown) admixture of basal and pulsatile release mechanisms, convolved with individually fitted biexponential elimination kinetics. This construct allows maximum-likelihood estimates of both (regulated and constitutive) components of hormone secretion. Thereby, we infer that a prolonged slow-component half-life of gonadotropin removal and amplified pulsatile (and total) daily luteinizing hormone (LH) secretion rates jointly explicate the postmenopausal elevation in serum LH concentrations without a necessary rise in basal LH secretion rates. This biomathematical formulation should be useful in exploring other neuroregulatory mechanisms that underlie single or dual alterations in the basal versus pulsatile modes of hormone secretion.

Joint recovery of pulsatile and basal hormone secretion by stochastic nonlinear random-effects analysis.

We present a nonlinear random-effects stochastic differential equation (SDE) model of combined basal and pulsatile hormone secretion with a series-specific hormone half-life and conditional pulse times. The construct uses a three-parameter pulse shape (generalized gamma function) to allow variably skewed secretory bursts superimposed on a finite basal hormone secretion rate. The analysis imbeds stochastic elements at three levels: a variable mass of hormone accumulation (of which the random effect is a part) during interpulse intervals, nonuniform secretion with hormone admixture into the circulation, and technical (sampling and assay) experimental uncertainty. We implement maximum likelihood estimates of secretory parameters (basal and pulsatile secretion and half-life) with asymptotic standard errors. The model applied to illustrative human luteinizing hormone (LH) time series suggests contrasts in basal LH secretion rates (e.g., greater in postmenopausal women than men) and LH secretory burst mass (e.g., higher in older women), but not LH burst frequency or distributional LH half-lives (7-40 min). For validation, in two infused (human recombinant) LH profiles, we implement partially constrained mono- and biexponential versions of the model with fixed (a priori assumed) versus variable LH basal secretion rates. We conclude that a statistically supported, nonlinear, random effects, SDE-based construct can evaluate jointly basal and pulsatile LH secretory rates and LH half-life in 24 h, episodically varying serum LH concentration profiles. This new reduced-parameter analytic strategy should be useful to explore further the pathophysiological mechanisms of altered neurohormone secretion.

A biomathematical model of time-delayed feedback in the human male hypothalamic-pituitary-Leydig cell axis.

We develop, implement, and test a feedback and feedforward biomathematical construct of the male hypothalamic [gonadotropin-releasing hormone (GnRH)]-pituitary [luteinizing hormone (LH)]-gonadal [testosterone (Te)] axis. This stochastic differential equation formulation consists of a nonstationary stochastic point process responsible for generating episodic release of GnRH, which is modulated negatively by short-loop (GnRH) and long-loop (Te) feedback. Pulsatile GnRH release in turn drives bursts of LH secretion via an agonistic dose-response curve that is partially damped by Te negative feedback. Circulating LH stimulates (feedforward) Te synthesis and release by a second dose response. Te acts via negative dose-responsive feedback on GnRH and LH output, thus fulfilling conditions of a closed-loop control system. Four computer simulations document expected feedback performance, as published earlier for the human male GnRH-LH-Te axis. Six other simulations test distinct within-model coupling mechanisms to link a circadian modulatory input to a pulsatile control node so as to explicate the known 24-h variations in Te and, to a lesser extent, LH. We conclude that relevant dynamic function, internodal dose-dependent regulatory connections, and within-system time-delayed coupling together provide a biomathematical basis for a nonlinear feedback-feedforward control model with combined pulsatile and circadian features that closely emulate the measurable output activities of the male hypothalamic-pituitary-Leydig cell axis.

Stochastic model of admixed basal and pulsatile hormone secretion as modulated by a deterministic oscillator.

Neuroendocrine ensembles communicate with their remote and proximal target cells via an intermittent pattern of chemical signaling. The lack of a biomathematical formulation of the underlying burst-generating mechanics of such pulsatile secretory systems has greatly hampered quantitative analysis of the physiological, pharmacological, and pathological regulation of the amplitude and frequency components of seemingly randomly dispersed neuroendocrine signals. Here we present a stochastic differential equation model of episodic glandular signaling in which random, but structured, variations in burst amplitudes superimposed on basal hormone release are combined with a nonstationary Poisson process responsible for the timing of scattered secretory bursts. Burst timing and/or amplitude can be modulated by underlying deterministic trends, e.g., circadian variations in mean expected neurosecretory burst frequency or mass. We illustrate the diversity of output of this model and suggest its use in extracting underlying properties of irregular biological signals in relevant hormone time series. This representation of episodic secretory behavior combines stochastic and deterministic elements inherent in the intermittent activity of a neuroendocrine apparatus.

Behavioral treatment of children with recurrent headaches.

The effectiveness of relaxation and biofeedback treatment for adults who suffer from headaches is well documented. By contrast, only several case study reports have been published describing these procedures applied to childhood headaches. This report describes the treatment of 15 children, aged 10-17 years, treated in a behavioral medicine clinic by using relaxation, biofeedback and behavioral counseling. At the end of treatment, 8 of 15 children were headache-free and 5 others exhibited a marked reduction in headache frequency and severity. Improvements were then maintained at follow-up. These results are comparable to results obtained when similar procedures are used to treat chronic adult headache sufferers.

Changes of blood metabolites in horses after racing, with particular reference to uric acid.

Changes in concentration of a number of blood metabolites in 30 thoroughbred horses were recorded after an 1110 metre race. No significant changes occurred in blood urea or aspartate aminotransferase during the three hours after racing. Plasma sodium, potassium and calcium levels were increased immediately after racing but had returned to normal one hour after racing. Plasma phosphate showed a significant fall in concentration one hour after racing. Creatinine and lactic acid concentrations were elevated ten minutes after racing and although they subsequently decreased, the level of lactic acid was still significant one hour later. Uric acid levels were well above resting levels at ten minutes after racing but rose even more in the subsequent hour. Urinary uric acid levels were also elevated during this time. Three hours after racing some horses still had elevated plasma uric acid levels and all of them showed a significant rise in creatine phosphokinase. The possible physiological basis of these findings is discussed.

Changes of plasma uric acid levels in horses after galloping.

Two horses were alternately galloped and cantered at 48 h intervals in a cross over trial. Galloping produced a rise in plasma lactic and uric acids. The lactic acid decreased in concentration whereas the uric acid increased in the hour after exercise. Plasma phosphate levels were depressed 1 h after galloping. There was no significant variation in these parameters after cantering. Possible reasons for these changes are discussed.