Enhanced basal and disorderly growth hormone secretion distinguish acromegalic from normal pulsatile growth hormone release.

Hartman, Mark L.; Pincus, Steve; Johnson, Michael L.; Matthews, Daniel; Faunt, Lindsay M.; Vance, Mary Lee; Thorner, Michael O.; Veldhuis, Johannes D.

doi:10.1172/jci117446

Cited by 213 publications

(147 citation statements)

References 57 publications

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“…In the present time series, we calculated crossApEn values with r ϭ 20% of the SD of the individual subject's hormone time series and m ϭ 1; for this, we hence use the designation X-ApEn(1,20%). This parameter set affords sensitive, valid, and statistically well-replicated ApEn (6,10,25,28) and cross-ApEn (30,40,43) metrics, which are stable to increasing experimental error or sampling frequency (28,47) in hormone time series assessments of this length. These aforementioned statistical evaluations include a variety of both broad-based theoretical analyses and numerous diverse applications, under (approximate) mean stationarity.…”

Section: Methodsmentioning

confidence: 85%

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

Liu¹,

Pincus²,

Keenan³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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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 concentrationconcentration 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.gonadal; adrenal; synchrony AGING IS MARKED BY A 30 -50% decline in systemic testosterone concentrations in healthy community-dwelling men, as recognized nearly 50 yr ago (11,46). Subsequent longitudinal (5,9,20) and population-based cross-sectional (2, 7, 19, 37) studies have corroborated relative androgen depletion in aging men. Other epidemiological data have correlated hypoandrogenemia with sarcopenia, osteopenia, reduced physical stamina, sexual dysfunction, impaired quality of life, and (possibly) depressive mood and cognitive impairment (46). Recent interventional studies suggest that reduced testosterone availability may be relevant to frailty in aging men (18,36). In parallel with therapeutic notions, mechanistic investigations are needed to determine why aging is associated with hypoandrogenemia. Few studies have appraised the effect of aging on nonlinear interactions, which are expected from time-delayed asymptotic dose-response connections among gonadotropin-releasing hormone (GnRH), LH, and testosterone. Recent developments of regulatory statistics and their validation in mathematical, laborat...

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Section: Methodsmentioning

confidence: 85%

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

Liu¹,

Pincus²,

Keenan³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Notably, eight surgically treated acromegalic patients studied by Hartman et al (4) showed intermediate irregularity, i.e. somewhat increased ApEn values and hence greater disorderliness compared with control subjects, yet with lower values than untreated patients (4). The purpose of the present study was to investigate in a considerably larger group of surgically treated acromegalic patients whether preoperatively disorganized GH secretion could normalize eventually after treatment.…”

Section: Introductionmentioning

confidence: 81%

“…ApEn provides a relative measure of pattern repetition within the hormone profile by assigning a single (positive) number whose value increases with greater disorder or more irregularity. This statistic exhibits high sensitivity (>90%) and specificity (>90%) in distinguishing the relative orderliness of GH, aldosterone, and ACTH release in normal vs tumoral secretory profiles and in the case of GH, in healthy men compared with women (4,8,9,18). For the GH time series each comprising 145 observations, we used ApEn(1,20%) and ApEn(2,20%) as a scale-and model-independent statistic calculated for window lengths (m) of 1 and 2 respectively, and a tolerance (r) of 20% of the overall S.D.…”

Section: Approximate Entropy Quantification Of Episodicitymentioning

confidence: 99%

“…Recent studies, applying a new regularity statistic, approximate entropy (ApEn), have revealed that the GH secretion pattern is also highly irregular (4,5,6). This inference has been supported further by other independent studies showing reduced predictability of GH release (by an adaptive neural network analysis) in acromegalic patients (7).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Reduced disorderliness of growth hormone release in biochemically inactive acromegaly after pituitary surgery

Berg

Pincus

Frölich

et al. 1998

European Journal of Endocrinology

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The episodicity of 24 h GH release was studied in 18 patients with active acromegaly, 12 patients 7-10 days after pituitary surgery, 14 patients long after operation (3-17 years), and 21 healthy gender-and age-matched control subjects, using a recently introduced scale-and model-independent regularity statistic, approximate entropy (ApEn). Blood samples were taken at 10-min intervals for 24 h, and plasma GH concentrations were measured by immunofluorometric assay (detection limit 11.5 ng/l). For this study we selected operated patients who were biochemically in remission, defined by normal circulating IGF-I and insulin-like growth factor-binding protein-3 (IGFBP-3) concentrations, normal glucose-suppressed plasma GH concentration (<0.38 mg/l), and the normalization of the paradoxical rise of GH to TRH or GnRH. In patients with active acromegaly ApEn was 1.23 Ϯ 0.04, with no overlap with the control subjects (P ¼ 1.2 × 10 ¹16 ), who had an ApEn of 0.40 Ϯ 0.04. ApEn in patients shortly after surgery was 0.71 Ϯ 0.09 (P < 0.001 vs controls), and long after surgery 0.56 Ϯ 0.05 (P < 0.011 vs controls). ApEn values in treated and untreated patients correlated significantly with the plasma concentration of IGF-I (r ¼ 0.531) and IGFBP-3 (r ¼ 0.598), and the log-transformed 24 h GH secretion rate (r ¼ 0.749). Shortly after surgery only one-third of the patients had a normal ApEn value, whereas long after surgery about 70% of the patients had a normal ApEn value. Although ApEn eventually normalized in about 70% of the operated patients, the cause of the persistence of abnormal GH release in the remainder of the subjects is not known, and might reflect permanent hypothalamic-pituitary dysfunction or a very early recurrence of the somatotroph adenoma.

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“…Approximate entropy is a recently introduced regularity statistics that measures the logarithmic likelihood that runs of patterns will be reproduced on next incremental comparison. The method has proved to be useful in a number of studies on hormonal secretion including growth hormone [95], LH [96], aldosterone [97], cortisol and ACTH [98,99], and recently insulin [36,64] to discriminate between pathophysiology and health. The method is robust to noise and to absolute differences in data.…”

Section: Methods For Assessing Pulsatile Insulin Secretionmentioning

confidence: 99%

The in vivo regulation of pulsatile insulin secretion

2002

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In 1922, Karen Hansen [1] measured two series of blood glucose concentrations and reported oscillations in the peripheral concentrations of this substrate, results which were validated by simultaneous sampling from two sites to exclude the possibility that assay variability was a cause of the observed variations. Furthermore she studied the glucose concentrations in diabetic patients, and described both rapid and slower oscillations [1]. Half a century later the observation of rapid oscillations was shown to correlate with oscillations in the peripheral insulin concentrations [2±6], with glucose concentration increases slightly out of phase with insulin secretion pulses [7]. The pulsatile secretion of insulin was shown to coincide with islet pulsatile release of glucagon [4,6,8,9], and somatostatin [9±11]. A number of studies have reported importance of this release pattern for optimal insulin action [10, 12±21, 21±25], for overall insulin secretion [26±35], and for possible development of disease [36±43]. Studies on pulsatile insulin secretion could therefore be important for appreciating how insulin release is regulated overall and how Diabetologia (2002) 45: 3±20 ReviewsThe in vivo regulation of pulsatile insulin secretion

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Enhanced basal and disorderly growth hormone secretion distinguish acromegalic from normal pulsatile growth hormone release.

Cited by 213 publications

References 57 publications

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

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

Reduced disorderliness of growth hormone release in biochemically inactive acromegaly after pituitary surgery

The in vivo regulation of pulsatile insulin secretion

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