ArticleLiterature Review

Orderliness of hormone release patterns: a complementary measure to conventional pulsatile and circadian analyses

May 1998
European Journal of Endocrinology 138(4):358-62

May 1998
138(4):358-62

DOI:10.1530/eje.0.1380358

Source
PubMed

Authors:

Steve Pincus

Massachusetts Institute of Technology

Ultradian Rhythmicity and Chaotic Behaviors in the Integrate-and-Fire Model of a Neuroendocrine System

Article

Full-text available

Nov 2022
INT J BIFURCAT CHAOS

We consider a mathematical model for pulsatility in a neuroendocrine regulation system. The impulsive neural activity is modeled using an integrate-and-fire mechanism, applied to ensembles of hypothalamic neurons. The system generates a discrete impulse-to-impulse mapping that can be used to detect periodic and chaotic behaviors. The numerical study of this mapping is illustrated with bifurcation diagrams. In a wide range of the model’s parameters, transition to chaos through cascades of period-doubling bifurcations was found. Merging and expansion bifurcations were also revealed in the system.

Actions of estrogen on pulsatile, nyctohemeral, and entropic modes of growth hormone secretion

Article

May 1999
Am J Physiol

The neuroendocrine mechanisms by which estradiol drives growth hormone (GH) secretion in the human are poorly defined. Here we investigate estrogen's specific regulation of the 24-h pulsatile, nyctohemeral, and entropic modes of GH secretion in healthy postmenopausal women. Volunteers (n = 9) received randomly ordered placebo versus estradiol-17beta (1 mg micronized steroid twice daily orally) treatment for 7-10 days and underwent blood sampling at 10-min intervals for 24 h to capture GH release profiles quantitated in a high-sensitivity chemiluminescence assay. Pulsatile GH secretion was appraised via deconvolution analysis, nyctohemeral GH rhythms by cosinor analysis, and the orderliness of GH release patterns via the approximate entropy statistic. Mean (+/-SE) 24-h serum GH concentrations approximately doubled on estrogen treatment (viz., from 0.31 +/- 0.03 to 0.51 +/- 0.07 microgram/l; P = 0.033). Concomitantly, serum insulin-like growth factor-I (IGF-I), luteinizing hormone, and follicle-stimulating hormone concentrations fell, whereas thyroid-stimulating hormone and prolactin levels rose (P < 0.01). The specific neuroendocrine action of estradiol included 1) a twofold amplified mass of GH secreted per burst, with no significant changes in basal GH release, half-life, pulse frequency, or duration; 2) an augmented amplitude and mesor of the 24-h rhythm in GH release, with no alteration in acrophase; and 3) greater disorderliness of GH release (higher approximate entropy). These distinctive and dynamic reactions to estrogen are consistent with partial withdrawal of IGF-I's negative feedback and/or accentuated central drive to GH secretion.

Developmentally Delimited Emergence of More Orderly Luteinizing Hormone and Testosterone Secretion during Late Prepuberty in Boys

Article

Full-text available

Feb 2001

To quantitate changing feedback control in the GnRH-LH/FSH-testosterone axis in male puberty, we here quantitate the orderliness of hormone release patterns using the regularity (pattern-sensitive) statistic, approximate entropy (ApEn), in 46 eugonadal boys representing 6 genitally defined stages of normal puberty. ApEn is a single variable, model-free, and scale-independent barometer of coordinate signaling or integrative regulation within a coupled neuroendocrine axis. Accordingly, we quantitated ApEn of LH profiles obtained by immunofluorometric assay of sera sampled every 20 min for 24 h. LH ApEn declined remarkably between early prepuberty (genital stage I-A: mean bone age, 4.6 +/- 1.6 yr; testis volume, <3 mL for at least 3 succeeding yr) and late prepuberty (genital stage I-C: bone age, 8.7 +/- 1.8 yr; testis volume, <3 mL for up to 1 yr thereafter; P: = 0.00019), which indicates the acquisition of more regular LH release patterns in late prepuberty. Maximal LH orderliness occurred in puberty stage II (bone age, 10.7 +/- 1.0 yr; testis volume, 2.8 +/- 0.4 mL). The LH secretory process was more disorderly in mid- and later puberty (Tanner stages III and IV). Transpubertal variations in testosterone ApEn manifested a similar tempo, i.e. the greatest regularity of testosterone secretion (lowest ApEn) emerged in Tanner genital stage II (P: < 10(-)(7)), with less orderly patterns evident both earlier and later in sexual development. In contrast, FSH ApEn values remained invariant of pubertal status. Analysis of bihormonal coupling using the theoretically related bivariate cross-ApEn statistic disclosed maximal 2-hormone synchrony for LH and testosterone secretion in genital stage II (P: = 0.031), with relative deterioration of coordinate LH and testosterone release patterns both before and after. LH and FSH release became maximally synchronous at the end of prepuberty (genital stage I-C; P: = 0.029), and FSH and testosterone synchrony peaked in pubertal stage III (P: = 0.037). As mean 24-h serum concentrations of LH, FSH, and testosterone rose transpubertally by 35-fold (LH), 68-fold (FSH), and 70-fold (testosterone), respectively, we infer that pubertal developmental stage per se rather than level of hormone output dictates coordinate GnRH-LH/FSH-testosterone secretion. In summary, in eugonadal boys, the regularity of 24-h LH and testosterone secretory patterns undergoes well defined pubertal stage-specific control. No sexually developmentally delimited regulation is inferable for FSH. The concept of temporally biphasic puberty-dependent variations in neurohormone secretory regularity contrasts with the unidirectional rise in daily hormone output. Accordingly, we infer that late prepuberty and early puberty (Tanner genital stages IC and II) embody a physiologically unique sexual developmental window, marked by transiently enhanced LH and testosterone feedback stability in boys. Whether analogous plasticity of hypothalamo-pituitary-gonadal interactions unfolds during female adolescence is not known.

Impact of age, sex and body mass index on cortisol secretion in 143 healthy adults

Article

Full-text available

Jul 2017

Context: Studies on 24-h cortisol secretion are rare. The impact of sex, age and adiposity on cortisol levels, often restricted to one or a few samples, are well recognized, but conflicting. Objective: To investigate cortisol dynamics in 143 healthy men and women, spanning 7 decades and with a 2-fold body mass index (BMI) range with different analytic tools. Setting: Clinical Research Unit. Design: Cortisol concentrations in 10-min samples collected for 24 h. Outcomes were mean levels, deconvolution parameters, approximate entropy (ApEn, regularity statistic), and 24-h rhythms. Results: Mean 24-h cortisol concentrations were lower in premenopausal women than men of comparable age (176±8.2 vs 217± 9.4 nmol/L, P=0.02), but not in subjects older than 50 y. This was due to lower daytime levels in women, albeit similar in the quiescent overnight period. Aging increased mean cortisol by 10 nmol/L per decade during the quiescent secretory phase, and advanced the acrophase of the diurnal rhythm by 24 min/decade. However, total 24-h cortisol secretion rates estimated by deconvolution analysis were sex-, age- and BMI-independent. ApEn of 24-h profiles was higher (more random) in premenopausal women than men (1.048±0.025 vs 0.933±0.023, P=0.001), but not in subjects older than 50 y. ApEn peaked during the daytime. Conclusion: Sex and age jointly determine the 24-h cortisol secretory profile. Sex effects are largely restricted to age <50 yr, whereas age effects elevate concentrations in the late evening and early night, and advance the timing of the peak diurnal rhythm.

Pulsatile Cortisol Feedback on ACTH Secretion Is Mediated by the Glucocorticoid Receptor and Modulated by Gender

Article

Aug 2016
J CLIN ENDOCR METAB

Context: Factors that regulate physiological feedback by pulses of glucocorticoids on the hypothalamic-pituitary unit are sparsely defined in humans in relation to gluco- or mineralocorticoid receptor pathways, gender, age and the sex-steroid milieu. Objective: To test (the clinical hypothesis) that glucocorticoid (GR) and mineralocorticoid (MR) receptor-selective mechanisms differentially govern pulsatile cortisol-dependent negative feedback on ACTH output( by the hypothalamo-pituitary unit) in men and women studied under experimentally defined testosterone (T) and estradiol (E2) depletion and repletion, respectively. Setting: Mayo Center for Translational Science Activities. Subjects: Healthy middle-aged men (N=16) and women (N=25). Interventions: Randomized, prospective, double-blind placebo- and saline-controlled study of pulsatile cortisol infusions in low cortisol-clamped volunteers with and without eplerenone (MR blocker) and mifepristone (GR blocker) administration under a low and normal T and E2 clamp. During frequent sampling, a bolus of CRH-AVP was infused to assess corticotrope responsiveness. Main outcome measures: Deconvolution and approximate entropy of ACTH profiles. Results: Infusion of cortisol (but not saline) pulses diminished ACTH secretion. The GR antagonist, mifepristone, interfered with negative feedback on both ACTH burst mass and secretion regularity. Eplerenone, an MR antagonist, exerted no detectable effect on the same parameters. Despite feedback imposition, CRH-AVP-stimulated ACTH secretion was also increased by mifepristone and not by eplerenone. Withdrawal vs addback of sex steroids had no effect on ACTH secretion parameters. Nonetheless, ACTH secretion was greater (P=0.006) and more regular (P=0.004) in men than women. Conclusion: Pulsatile cortisol feedback on ACTH secretion in this paradigm is mediated by the glucocorticoid receptor, in part acting at the level of the pituitary, and influenced by sex.

Secretory process regularity monitors neuroendocrine feedback and feedforward signaling strength in humans

Article

Full-text available

Mar 2001

The present experiments examine the neuroregulatory hypothesis that the degree of sample-by-sample regularity of hormone output by an interlinked hypothalamopituitary target-organ system monitors the strength of feedback and/or feedforward signaling. To test this postulate and assess its generality, we implemented a total of nine thematically complementary perturbation experiments. In particular, we altered feedback or feedforward signaling selectively in two distinct neuroendocrine systems; namely, the growth hormone (GH) insulin-like growth factor type I (IGF-I) and the luteinizing hormone-testosterone axes. Four experimental paradigms comprised preferential reduction vs. enhancement of IGF-I or testosterone feedback signal strength; and, conversely, five others entailed selective attenuation vs. augmentation of GH-releasing hormone and gonadotropin-releasing hormone feedforward signal intensity. In these independent interventions, quantitation of subordinate (nonpulsatile) secretory pattern reproducibility via the approximate entropy statistic unmasked salient changes (P values typically <10(-3)) in the conditional regularity of serial hormone output with high consistency (96-100%). In particular, approximate entropy quantified degradation of secretory subpattern orderliness under either muted feedback restraint or heightened feedforward drive. Assuming valid interpretation of the biological constraints imposed, these experimental observations coincide with earlier reductionist mathematical predictions, wherein increased irregularity of coupled parameter output mirrors attenuated feedback and/or augmented feedforward coupling within an integrative system.

Disruption of the Synchronous Secretion of Leptin, LH, and Ovarian Androgens in Nonobese Adolescents with the Polycystic Ovarian Syndrome

Article

Full-text available

Aug 2001

The present study probes putative disruption of hypothalamic control of multihormone outflow in polycystic ovarian syndrome by quantitating the joint synchrony of leptin and LH release in adolescents with this syndrome and eumenorrheic controls. To this end, hyperandrogenemic oligo- or anovulatory patients with polycystic ovarian syndrome (n = 11) and healthy girls (n = 9) underwent overnight blood sampling every 20 min for 12 h to monitor simultaneous secretion of leptin (immuno-radiometric assay), LH (immunofluorometry), and androstenedione and T (RIA). Synchronicity of paired leptin-LH, leptin-androstenedione, and leptin-T profiles was appraised by two independent bivariate statistics; viz., lag-specific cross-correlation analysis and pattern-sensitive cross-approximate entropy. The study groups were comparable in chronological and postmenarchal age, body mass index, fasting plasma insulin/glucose ratios, and serum E2 concentrations. Overnight mean (+/- SEM) serum leptin concentrations were not distinguishable in the two study groups at 30 +/- 4.8 (polycystic ovarian syndrome) and 32 +/- 7.4 microg/liter (control). Serum LH concentrations were elevated at 9.5 +/- 1.4 in girls with polycystic ovarian syndrome vs. 2.8 +/- 0.36 IU/liter in healthy subjects (P = 0.0015), androstenedione at 2.8 +/- 0.30 (polycystic ovarian syndrome) vs. 1.2 +/- 0.11 ng/ml (control) (P = 0.0002), and T at 1.56 +/- 0.29 (polycystic ovarian syndrome) vs. 0.42 +/- 0.06 ng/ml (P < 0.0001). Cross-correlation analysis shows that healthy adolescents maintained a positive relationship between leptin and LH release, wherein the latter lagged by 20 min (P < 0.01). No such association emerged in girls with polycystic ovarian syndrome. In eumenorrheic volunteers, leptin and androstenedione concentrations also covaried in a lag-specific manner (0.0001 < P < 0.01), but this linkage was disrupted in patients with polycystic ovarian syndrome. Anovulatory adolescents further failed to sustain normal time-lagged coupling between leptin and T (P < 0.01). Approximate entropy calculations revealed erosion of orderly patterns of leptin release in polycystic ovarian syndrome (P = 0.012 vs. control). Cross-entropy analysis of two-hormone pattern regularity disclosed marked disruption of leptin and LH (P = 0.0099), androstenedione and leptin (P = 0.0075) and T-leptin (P = 0.019) synchrony in girls with polycystic ovarian syndrome. In summary, hyperandrogenemic nonobese adolescents with oligo- or anovulatory polycystic ovarian syndrome manifest: 1) abrogation of the regularity of monohormonal leptin secretory patterns, despite normal mean serum leptin concentrations; 2) loss of the bihormonal synchrony between leptin and LH release; and 3) attenuation of coordinate leptin and androstenedione as well as leptin and T output. In ensemble, polycystic ovarian syndrome pathophysiology in lean adolescents is marked by vivid impairment of the synchronous outflow of leptin, LH and androgens. Whether analogous disruption of leptin-gonadal axis integration is ameliorated by therapy and/or persists into adulthood is not known.

Interleukin-2 Transiently Inhibits Pulsatile Growth Hormone Secretion in Young but not Older Healthy Men

Article

Jul 2021

Context Interleukin-2 (IL2), a proinflammatory cytokine, has been used to treat malignancies. Increased cortisol and ACTH were noted, but GH secretion was not investigated in detail. Objective We quantified GH secretion after a single sc injection of IL2 in 17 young and 18 older healthy men in relation to dose, age and body composition. Design This was a placebo-controlled, blinded, prospectively randomized cross-over study. At 20:00 h IL2 (3 or 6 million units per m2 ) or saline was injected sc. Lights were off between 23:00 and 07:00 h. Blood was sampled at 10-min intervals for 24 h. Outcome measures Deconvolution analysis of GH secretion. Results GH profiles were pulsatile under both experimental conditions and lower in older than young volunteers. Since the effect of IL2 might be time-limited, GH analyses were performed on the complete 24-h series and the 6 h after IL2 administration. Total and pulsatile 24-h GH secretion decreased nonsignificantly. Pulsatile secretion fell over the first 6 h after IL2 (P=0.034), with visceral fat as covariate (P=0.003), but not age(P=0.10). Plots of cumulative 2-h bins of GH pulse mass showed a distinction by treatment and age groups: a temporary GH decrease of 32% and 28% occurred in the first 2-h bins after midnight (P=0.019 and 0.038) in young subjects, while in older subjects no differences were present at any time point. Conclusion This study demonstrates that IL2 temporarily diminishes GH secretion in young, but not elderly, men.

Interleukin-2 drives pulsatile cortisol secretion in an age-, dose- and body composition-dependent way in healthy men

Article

Feb 2020

Johannes D Veldhuis

Enhanced Coupling Within Gonadotropic and Adrenocorticotropic Axes by Moderate Exercise in Healthy Men

Article

Apr 2017

Context: Exercise elicits incompletely defined adaptations of metabolic and endocrine milieu, including the gonadotropic and the corticotropic axes. Objective: To quantify the impact of acute exercise on coordinate LH and testosterone and ACTH and cortisol secretion in healthy men in relation to age. Participantsand design: Prospectively randomized, within-subject cross-over, study in 23 men, aged 19-77 yr. Subjects underwent rest and 30 min of mixed exercise at 65% of maximal aerobic capacity with 10-min blood sampling between 0700 and 1300 h 2 wks apart. Main outcome measures: Incremental changes in LH, testosterone, ACTH and cortisol concentrations, the feedforward and feedback strength between exercise and rest, quantified by approximate entropy (ApEn), and bihormonal synchrony, quantitated by cross ApEn. Results: Mean hourly exercise-minus-rest LH and ACTH increments increased from -0.055±0.187 to 0.755±0.245 IU/L (P=0.003), and from 2.9±2.2 to 71.2±16.1 ng/L (P<0.0001), respectively, during exercise. Testosterone and cortisol increments increased concurrently from -9.6±16.7 to 47.6±17.1 ng/dL (P<0.0001), and 0.45±0.76 to 7.27±0.64 µg/dL (P<0.0001), respectively. During exercise, feedforward as well as feedback LH-testosterone and ACTH-cortisol cross-ApEn decreased markedly quantifying enhanced hormonal coupling. These dynamic adaptations did not correlate with age, visceral fat, power expended, or estradiol, testosterone, adiponectin, IGF-I, cortisol and TSH. Conclusion: Acute moderate mixed exercise in healthy men rapidly enhances feedforward LH-T and ACTH-cortisol coordination and reciprocal feedback within the gonadotropic and corticotropic axes. In principle, enhancement of both LH-T and ACTH-cortisol secretory synchrony by exercise could reflect augmented coupling between brain-testicular and brain-adrenal neural outflow.

Impact of Sleep and Its Disturbances on Hypothalamo-Pituitary-Adrenal Axis Activity

Article

Full-text available

Jan 2010

The daily rhythm of cortisol secretion is relatively stable and primarily under the influence of the circadian clock. Nevertheless, several other factors affect hypothalamo-pituitary-adrenal (HPA) axis activity. Sleep has modest but clearly detectable modulatory effects on HPA axis activity. Sleep onset exerts an inhibitory effect on cortisol secretion while awakenings and sleep offset are accompanied by cortisol stimulation. During waking, an association between cortisol secretory bursts and indices of central arousal has also been detected. Abrupt shifts of the sleep period induce a profound disruption in the daily cortisol rhythm, while sleep deprivation and/or reduced sleep quality seem to result in a modest but functionally important activation of the axis. HPA hyperactivity is clearly associated with metabolic, cognitive and psychiatric disorders and could be involved in the well-documented associations between sleep disturbances and the risk of obesity, diabetes and cognitive dysfunction. Several clinical syndromes, such as insomnia, depression, Cushing's syndrome, sleep disordered breathing (SDB) display HPA hyperactivity, disturbed sleep, psychiatric and metabolic impairments. Further research to delineate the functional links between sleep and HPA axis activity is needed to fully understand the pathophysiology of these syndromes and to develop adequate strategies of prevention and treatment.

The Effect of Virtual Reality on Gait Variability

Article

Full-text available

Jul 2010
Nonlinear Dynam Psychol Life Sci

Optic Flow (OF) plays an important role in human locomotion and manipulation of OF characteristics can cause changes in locomotion patterns. The purpose of the study was to investigate the effect of the velocity of optic flow on the amount and structure of gait variability. Each subject underwent four conditions of treadmill walking at their self-selected pace. In three conditions the subjects walked in an endless virtual corridor, while a fourth control condition was also included. The three virtual conditions differed in the speed of the optic flow displayed as follows--same speed (OFn), faster (OFf), and slower (OFs) than that of the treadmill. Gait kinematics were tracked with an optical motion capture system. Gait variability measures of the hip, knee and ankle range of motion and stride interval were analyzed. Amount of variability was evaluated with linear measures of variability--coefficient of variation, while structure of variability i.e., its organization over time, were measured with nonlinear measures--approximate entropy and detrended fluctuation analysis. The linear measures of variability, CV, did not show significant differences between Non-VR and VR conditions while nonlinear measures of variability identified significant differences at the hip, ankle, and in stride interval. In response to manipulation of the optic flow, significant differences were observed between the three virtual conditions in the following order: OFn greater than OFf greater than OFs. Measures of structure of variability are more sensitive to changes in gait due to manipulation of visual cues, whereas measures of the amount of variability may be concealed by adaptive mechanisms. Visual cues increase the complexity of gait variability and may increase the degrees of freedom available to the subject. Further exploration of the effects of optic flow manipulation on locomotion may provide us with an effective tool for rehabilitation of subjects with sensorimotor issues.

Variability of Lower Extremity Joint Kinematics During Backward Walking in a Virtual Environment

Article

Full-text available

Apr 2010
Nonlinear Dynam Psychol Life Sci

Backward walking (BW) shows significant differences with forward walking (FW) and these differences are potentially useful in rehabilitation. However the lack of visual cues makes BW risky. The purpose of this study was to investigate the effect of visual cues provided by a virtual environment on FW and BW on gait variability. Each subject underwent four conditions of treadmill walking at self-selected pace. The subjects walked backwards in three conditions and forwards in the fourth condition. A virtual corridor was displayed to the subjects in the FW condition (forward optic flow) and two of the backward conditions (forward and backward optic flow). The third BW condition was a control condition (no visual cues). Gait variability measures of the hip, knee and ankle range of motion and the stride interval were analyzed. Magnitude of variability was evaluated with the coefficient of variation and structure of variability with approximate entropy. Significant differences were demonstrated between the FW and the BW gait characteristics as well as in gait variability (for both magnitude and structure of variability). No significant differences were found between the three BW conditions as a result of the direction of visual cues. In order to get optimal benefit of BW in the aged and the diseased, optical flow of visual feedback may need to be manipulated in a different manner than FW. Future studies will explore other parameters of visual cues like the velocity of optic flow and appearance of obstacles to obtain the best visual cue configuration for rehabilitation.

Cortisol and GH secretory dynamics, and their interrelationships, in healthy aged women and men

Article

Full-text available

Apr 2001

We studied 130 healthy aged women (n = 57) and men (n = 73), age 65-88 yr, with age-related reductions in insulin-like growth factor I and gonadal steroid levels to assess the interrelationships between cortisol and growth hormone (GH) secretion and whether these relationships differ by sex. Blood was sampled every 20 min from 8:00 PM to 8:00 AM; cortisol was measured by RIA and GH by immunoradiometric assay, followed by deconvolution analyses of hormone secretory parameters and assessment of approximate entropy (ApEn) and cross-ApEn. Cortisol mass/burst, cortisol production rate, and mean and integrated serum cortisol concentrations (P < 0.0005), and overnight basal GH secretion (P < 0.05), were elevated in women vs. men. Integrated cortisol concentrations were directly related to most measures of GH secretion in women (P < 0.01) and with mean and integrated GH concentrations in men (P < 0.05). Integrated GH concentrations were directly related to mean and integrated cortisol levels in women (P < 0.005) and men (P < 0.05), with no sex differences. There were no sex differences in cortisol or GH ApEn values; however, the cross-ApEn score was greater in women (P < 0.05), indicating reduced GH-cortisol pattern synchrony in aged women vs. men. There were no significant relationships of integrated cortisol secretion with GH ApEn, or vice versa, in either sex. Thus postmenopausal women appear to maintain elevated cortisol production in patterns that are relatively uncoupled from those of GH, whereas mean hormone outputs remain correlated.

Basal, Pulsatile, Entropic, and 24-Hour Rhythmic Features of Secondary Hyperprolactinemia Due to Functional Pituitary Stalk Disconnection Mimic Tumoral (Primary) Hyperprolactinemia

Article

Full-text available

Apr 2001

Under physiological conditions, PRL secretion is regulated precisely by various stimulating and inhibiting factors. Hyperprolactinemia may arise as a primary consequence of a PRL-secreting pituitary adenoma. Secondary hyperprolactinemia (SH) may emerge in patients with hypothalamic disease, hypophyseal stalk compression, or suprasellar extension of a (nonlactotrope) pituitary adenoma. The latter may reflect diminished delivery of dopamine or other inhibitory factors to normal lactotropes. We hypothesized that diurnal and ultradian rhythms of PRL secretion would differ in secondary (e.g. hypothalamic) and primary (e.g. tumoral states) hyperprolactinemia (PH), assuming that the underlying pathophysiologies differ. To test this clinical postulate, we investigated the patterns of 24-h PRL release in eight patients with SH associated with functional hypothalamo-pituitary disconnection and in eight patients with PH attributable to microprolactinoma. Data in each group were compared with values in healthy gender-matched controls. PRL time series were obtained by repetitive 10-min blood sampling, followed by high- precision immunofluorometric assay. PRL concentration profiles were analyzed by the complementary tools of model-free discrete peak detection, waveform-independent deconvolution analysis, cosinor regression, and the approximate entropy metric to quantitate pulsatile, basal, 24-h rhythmic, and pattern-dependent (entropic) PRL secretion. Patients with tumoral hyperprolactinemia (PH) showed a 2-fold higher 24-h mean serum PRL concentration than patients with SH (62 +/- 13 microg /L vs. 30 +/- 6.9 microg/L, respectively, P = 0.029). Estimated PRL pulse frequency (events/24 h) was similar in the two patient groups (18.5 +/- 0.7 vs. 17.6 +/- 0.8; P = 0.395) but elevated over that in euprolactinemic controls (P < 0.0001 for both). Deconvolution analysis disclosed a mean daily PRL secretion rate of 790 +/- 170 microg in PH patients vs. 380 +/- 85 microg in SH patients (P = 0.030). Nonpulsatile PRL secretion comprised nearly 70% of total secretion in both patient groups and 50% in controls (P < 0.0001). Cosinor analysis revealed similar acrophases in all three study cohorts. The mean skewness of the statistical distribution of the individual PRL sample secretory rates was reduced, compared with controls (P < 10 (-5) for each), but equivalent in SH and PH patients (0.83 +/- 0.12 vs. 0.78 +/- 0.08, respectively), denoting a loss of the normal spectrum of low- and higher-amplitude secretion rates. Approximate entropy, a regularity statistic, was markedly elevated in both patient groups over controls (P < 10 (-6) for each) and was slightly higher in PH patients than in SH patients (1.639 +/- 0.029 vs. 1.482 +/- 0.067, P = 0.048). In summary, patterns of PRL secretion in PH and SH states exhibit an equivalently increased frequency of PRL pulses, a comparably marked rise in nonpulsatile (basal) PRL secretion. Despite overlap, the regularity of PRL release patterns is disrupted even more profoundly in PH (tumoral), compared with SH. Assuming that the orderliness of serial PRL output monitors normal integration within a feedback-controlled neurohormone axis, then the more disorderly patterns of tumoral PRL secretion point to greater regulatory disruption in PH. The latter may reflect abnormal secretory behavior associated with lactotrope neoplastic transformation and/or isolation of the tumor cell mass from normal hypothalamic controls.

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

Article

Full-text available

Jul 2001

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.

Intensive Direct Cavernous Sinus Sampling Identifies High-Frequency, Nearly Random Patterns of FSH Secretion in Ovariectomized Ewes: Combined Appraisal by RIA and Bioassay

Article

Full-text available

Feb 2002

Analyses of FSH secretion suggest pulsatile, nonpulsatile, or compositely pulsatile and nonpulsatile release modes. This may reflect the reduced signal-to-noise ratio inherent in FSH pulse estimation procedures and/or immunological-biological assay inconsistencies. To address these issues, we sampled cavernous sinus and jugular venous blood concomitantly from ovariectomized sheep at either 5-min or 1-min intervals. Samples from the former were assayed by RIA, and those from the latter by RIA and bioassay. Waveform-independent peak detection revealed FSH pulses occurring at high frequency. Pulsatile FSH secretion accounted for 28% of total secretion. Approximate entropy analysis showed that FSH secretion was nearly random. There was synchronous release of LH and FSH, but most FSH secretion was not associated with LH release; 13% of discrete FSH and LH pulses were concordant. We infer that FSH secretion exhibits pulsatile and basal/nonpulsatile features, with high-entropy features. Linear and nonlinear statistical measures revealed joint sample-by-sample synchrony of FSH and LH release, indicating pattern coordination despite sparse synchrony of pulses. We postulate that pattern synchrony of FSH and LH release is effected at the level of the gonadotrope. Concordant FSH and LH pulses probably result from pulsatile GnRH input, but other mechanisms could account for independent FSH pulses.

Interleukin-2 drives cortisol secretion in an age-, dose- and body composition-dependent way

Article

Full-text available

Jun 2020

Background: Interleukin-2 (IL-2), one of the proinflammatory cytokines, is used in the treatment of certain malignancies. In some studies, transient increases in cortisol and ACTH secretion occurred. Thus, this agent may be used as an experimental probe of adrenal cortisol secretion. Objective: This study quantifies effects of low and moderate doses of IL-2 on cortisol secretion, and assesses the modulation by age, dose and body composition. Site: Mayo Clinical Translational Research Unit. Subjects: Study comprised 35 healthy men, 17 young and 18 older. Methods: Randomized prospective double-blind saline-controlled study of IL-2 administration in 2 doses with concurrent 10-min blood sampling for 24 h. Outcome measures: Deconvolution analysis and Approximate Entropy of cortisol secretion. Results: Low dose IL-2 administration increased nocturnal pulsatile cortisol secretion from 1460±160 to 2120±220 nmol/L/8h in young subjects and from 1680±105 to 1960±125 nmol/L/8h (treatment P<0.0001, but more in young than older, P=0.02). Comparable results were obtained for total cortisol secretion (P treatment <0.0001, age effect P=0.005). The higher IL2 dose caused a large increase in young (P<0.0001), but not in older (P=0.90) subjects. This dose also increased approximate entropy from 0.877±0.041 to 1.024±0.049 (P=0.008), pointing to reduced secretory orderliness. Incremental cortisol (nocturnal) secretion correlated negatively with visceral fat mass (R=-0.41, P=0.019). Conclusion: In healthy men, IL-2 injection drives pulsatile cortisol secretion in a dose-dependent way in young, but not older, individuals, and erodes cortisol secretory orderliness at a higher dose in young subjects. Cortisol responses are diminished with increasing abdominal visceral fat mass.

Dynamical Aspects of Pharmacokinetic/Pharmacodynamic & Quantitative Systems Pharmacology Models

Chapter

Apr 2020

Physiological systems are inherently dynamic and complex. The erratic nature and the irregular behavior of these systems has been the subject of several studies in the field of systems biomedicine. In human physiology, complex phenomena such as heart rate variability are often associated with the maintenance of homeostasis, whereas loss of complexity is perceived as indication of pathology. In pharmacology, the response of a physiological system to external perturbations (i.e. drug) can be studied with pharmacokinetic/pharmacodynamic (PK/PD) and quantitative systems pharmacology (QSP) models. However, analysis of the underlying dynamics of such models is often ignored. In this chapter, the presence of nonlinear dynamics in physiological and pharmacological systems is highlighted through a summary of specific applications in various therapeutic areas. In parallel, the additive benefit of implementing tools borrowed from dynamical systems’ theory to gain insight into the behaviour of PK/PD and QSP models is also underlined.

An Ensemble Perspective of Aging-Related Hypoandrogenemia in Men

Chapter

Apr 2017

Aging is associated with changes in pituitary testicular function in men which are partly explained by changes in the testis and by comorbidities, body weight, nutrition, and the presence of diabetes mellitus. The 0.8–1.3% annual fall in nonSHBG bound “bioavailable” testosterone levels results in a reduction of 30–50% by the sixth to eighth decades of life. Low testosterone concentrations are associated with relative sarcopenia, osteopenia, visceral fat accumulation, reduced sexual function, detectable cognitive impairment, and variable depression of mood. Accordingly, the mechanisms driving the progressive decline in androgens are important to understand. To this end, we highlight age-associated alterations in three dominant sites of physiological control; viz., the hypothalamus, pituitary gland, and testis. The cognate signals are gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and testosterone, which jointly determine androgen availability via feedback and feedforward adaptations. According to this emergent notion, no single gland acts in isolation to maintain homeostasis. We underscore an integrative concept by highlighting how aging-related testosterone depletion is an ensemble outcome of deterioration of interlinked control.

Restoration of High-Frequency Glucose Entrained Insulin Oscillations in Obese Subjects with Type 2 Diabetes Mellitus Following BPD

Article

Apr 2016

Background: Minimal glucose infusions are known to entrain insulin oscillations in patients with normal glucose tolerance (NGT) but not in patients with type 2 diabetes (T2D). Objectives: To investigate whether weight loss after a version of biliopancreatic diversion (BPD) can restore the glucose entrainment of high-frequency insulin oscillations in morbidly obese NGT or T2D patients. Setting: University Hospital, Greece. Methods: We prospectively studied 9 NGT controls (body mass index [BMI] 23.3±1.6 kg/m(2)), 9 obese NGT patients (BMI 51.1±12.7 kg/m(2)), and 9 obese T2D patients (BMI 56.8±11.6 kg/m(2)). Patients were studied before and 1.5 years after BPD. Insulin was sampled every minute for 90 minutes. Glucose (6 mg/kg weight) was infused every 10 minutes for 1 minute. Regularity of insulin pulses was estimated by autocorrelation analysis, spectral analysis, approximate entropy/sample entropy (ApEn/SampEn), and insulin pulsatility by deconvolution analysis. Results: Postoperatively, glucose and insulin concentrations of NGT and T2D patients decreased to control levels and BMI to 31.3±6.3 for NGT patients and 34.9±9.9 kg/m(2) for T2D patients. Preoperatively, glucose entrainment was absent in all T2D and in 4 NGT patients as assessed with spectral analysis and in 8 and 4, respectively, as assessed with autocorrelation and deconvolution analysis. Postoperatively, it was restored to normal in all patients. ApEn/SampEn decreased significantly only in the T2D group postoperatively. Conclusion: BPD restores the glucose entrainment of high-frequency insulin oscillations in obese NGT and T2D patients after marked weight loss and normalizes glucose levels and insulin sensitivity, thus demonstrating recovery of β-cell glucose sensing.

An Ensemble Perspective of Aging-Related Hypoandrogenemia in Men

Chapter

Jan 2004

The aging process is marked by a relatively subtle short-term decline in reproductive hormone outflow in men. However, the nominal 0.8–1.3% annual fall in systemic bioavailability of testosterone results in a reduction of 30–50% by the sixth through eighth decades of life. Low testosterone concentrations forecast relative sarcopenia, osteopenia, visceral fat accumulation, detectable cognitive impairment, and variable mood depression. Accordingly, the mechanisms driving progressive androgen deprivation are important to understand. To this end, age-associated alterations in three dominant sites of physiological control, namely the hypothalamus, pituitary gland, and testis, are highlighted. The cognate signals are gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and testosterone, which jointly determine androgen availability via feedback and feedforward adaptations. According to this emergent notion, no single gland acts in isolation to maintain homeostasis. An integrative concept is underscored by highlighting how aging-related testosterone depletion is an ensemble outcome of deterioration of interlinked control.

Proposed Mechanisms of Sex-Steroid— Hormone Neuromodulation of the Human GH—IGF-I Axis

Chapter

Jan 1999

Sex-steroid hormones are integral to pubertal development in boys and girls, and sustain sexual function and body composition throughout the human lifetime (1–14). A corollary tenet of human physiology in both the male and female is that sex steroids interact with the growth-promoting GH—IGF-I axis at multiple loci of control (15–17). Although this presentation focuses on the hypothalamopituitary actions of estrogen and androgen in modulating output of the GH—IGF-I axis, other important sites of sex-steroid-GH interplay also operate in health and disease, such as at the levels of the gonad, the IGF- I-binding proteins, GH-receptor expression, and target tissues such as fat, muscle, and bone (18). Extensive experimental data in the rodent further establish sex-steroid-GH axis interactions throughout the pre- and postpu- bertal lifetimes (19,20). The present symposial update primarily highlights issues explored recently in human-based investigations of sex hormone—GH axis interactions. We also identify some of the exciting and as yet unad- dressed challenges within this clinical neuroendocrine theme.

Disruption of the Synchronous Secretion of Leptin, LH, and Ovarian Androgens in Nonobese Adolescents with the Polycystic Ovarian Syndrome

Article

Aug 2001

J. D. Veldhuis

Growth hormone and prolactin are secreted more irregularly in patients with Cushing disease

Article

May 2000
CLIN ENDOCRINOL

OBJECTIVE To investigate whether the spontaneous secretion of growth hormone and prolactin in adult patients with pituitary-dependent Cushing's disease is decreased.PATIENTSFourteen adult patients (9 women, 5 men; age: 34 ± 3.4 years, mean ± SEM) with pituitary-dependent Cushing's disease and 14 controls matched for age, gender and body mass index were studied.METHODS Blood samples were withdrawn at 10 minutes intervals starting at 0900 h for 24 h. GH and PRL release were quantified with deconvolution methods. The regularity of GH and PRL release was measured with approximate entropy statistics.RESULTSThe number of GH secretory events per 24 h was higher in patients than in controls: 19 ± 1.3 vs. 14 ± 1.5 peaks per 24 h, respectively (P = 0.020). GH secretion rate was about one quarter lower in patients (ns), and the 24 h secretion of PRL was unchanged. Total GH production correlated negatively with the urinary excretion of free cortisol (R = 0.729, P = 0.005) and with the plasma cortisol production rate (R = 0.613; P = 0.026).The orderliness of GH and PRL secretion was appraised with the approximate entropy statistic (ApEn). For GH secretion ApEn(1,20%) in patients was 0.952 ± 0.084 vs. 0.404 ± 0.047 in controls, P = 1.17 × 10−4, pointing to a markedly disordered secretion in patients. Similar results were obtained for PRL secretion: patients: 1.586 ± 0.063 vs. 1.003 ± 0.068 in controls, P = 3.67 × 10−5. No statistically significant differences in secretory dynamics were demonstrated between the 10 patients with a microadenoma and the four with a macroadenoma.CONCLUSION The amount of GH released spontaneously into the circulation in adult patients with pituitary-dependent Cushing's disease is inversely related to the degree of cortisol hypersecretion. However, except for severe hypercortisolism, GH secretion is relatively preserved. In addition, secretion of GH and PRL is remarkably disordered in patients with Cushing's disease. Since we could not detect differences in GH and/or PRL secretory dynamics between patients with a microadenoma and those harboring a macroadenoma, we speculate that an intrapituitary paracrine mechanism and/or elevated cortisol feedback effects may be responsible for the evident disruption of GH and PRL secretion patterns.

Neuroendocrine adaptations in renal disease

Article

Jul 2003

Chronic renal failure (CRF) disrupts the time-dependent secretion of multiple hormones. The present review focuses on altered pulsatile release of peptide hormones. CRF is marked by impaired tissue actions, disorderly release patterns, and relative [growth hormone (GH)] or absolute [luteinizing hormone (LH)] deficiency of secretion. At the hypothalamo-pituitary level, experimental evidence suggests that CRF reduces the synthesis and/or release of the cognate hypothalamic releasing factors, GHRH and LHRH, and enforces excessive inhibition by somatostatin. Parathyroid hormone (PTH) and insulin are secreted in both basal and pulsatile modes, wherein the latter is putatively coordinated by autonomic innervation. Amplitude and frequency-dependent adaptations of PTH and insulin outflow fail in CRF, as assessed under steady-state conditions and during metabolic drive (i.e., calcium for PTH and glucose for insulin). A common feature in CRF is a diminished mass of hormone released per burst, due in principle to attenuation of feedforward signals and/or accentuation of (unknown) feedback signals. Damping of neuronal control and/or prolonged network response times may contribute to aberrant pulse frequency, disproportionate basal (nonpulsatile) hormone release, and consistent erosion of secretory process regularity in the uremic state. The homeostatic consequences of distorted secretory dynamics, tissue resistance, impaired hormone clearance, and altered mean agonist concentrations are evident in certain therapeutic interventions, such as GH supplementation in CRF.

Neuroendocrine perturbations in human obesity

Article

Petra Kok

The evolutionary advantage to conserve energy in the form of adipose issue in order to survive long periods of food shortage in the past, turned into a major health problem in current times of plenty. Excess accumulation of body fat, or “obesity”, is associated with severely increased co-morbidity and mortality risks and is a global epidemical medical condition which is difficult to manage. The exact pathophysiologic mechanism of obesity remains elusive and various factors such as genetic, social, behavioral and physiological cues are involved in its development. From a biological point of view, obesity might be partly explained by differences in the regulation of energy intake, expenditure and storage (energy homeostasis) between obese and lean individuals. The neuroendocrine system provides a source of humoral messengers, which modulate energy homeostasis. This thesis will focus on changes of the neuroendocrine environment of obese women. First of all, spontaneous diurnal plasma hormone concentrations and secretion of different hormonal systems were studied. Secondly, the effect of weight loss on neuroendocrine perturbations of some of these hormonal axes was evaluated. Finally, the impact of modulation of potential physiological cues (increased circulating FFAs and deficit dopaminergic signaling), which might be involved in the neuroendocrine changes and metabolic alterations, was investigated.

Olanzapine shifts the temporal relationship between the daily acrophase of serum prolactin and cortisol concentrations rhythm in healthy men

Article

Feb 2009

Treatment with the atypical antipsychotic drug olanzapine is frequently associated with development of obesity and insulin resistance. Treatment-induced weight gain has been suggested to be the main contributing factor of diminished insulin sensitivity. This study evaluated the effects of short-term treatment with olanzapine on 12h plasma prolactin and cortisol concentrations in healthy men. The effects of two distinct olanzapine formulations were investigated; the oral standard tablets (OST) and the orally disintegrating tablets (ODT). Recent reports indicate that treatment with the ODT formulation may be less harmful in terms of weight gain than the OST. 12 healthy men (age: 25.1+/-5.5 y) received olanzapine OST (10mg QD, 8 days), olanzapine ODT (10mg QD, 8 days) or no intervention in a randomized cross-over design. On day 8, blood samples were taken every 10min between 0000 and 1200h for determination of cortisol and prolactin concentrations. Treatment with olanzapine OST and ODT similarly increased the 12h mean PRL concentrations and the secreted PRL mass. Both drugs similarly shifted the maximal PRL concentration approximately 3-4h backwards in time. Cortisol secretions rates were lower, but the timing of the cortisol acrophase did not change. Both drugs significantly elevated HOMA index for insulin resistance. In conclusion olanzapine OST and ODT equally elevated the prolactin concentration and significantly shifted its acrophase, thus dissociating PRL and cortisol, while both formulations induced similar insulin resistance as evidenced by the elevated HOMA-IR. Notably, these alterations occurred without a measurable effect on body adiposity.

Motivations and Methods for Analyzing Pulsatile Hormone Secretion

Article

Nov 2008

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.

Postoperative metyrapone test in the early assessment of outcome of pituitary surgery for Cushing's disease

Article

Aug 1997

The prediction of relapse during the early months after transsphenoidal surgery for Cushing's disease remains difficult. We have evaluated the usefulness of the postoperative metyrapone test in this situation. From a retrospective series of 77 consecutive primary pituitary operations for Cushing's disease 29 patients, who also had a metyrapone test at 14 days postoperatively, were selected. Median follow-up was 35 months (range: 8-118 months). Early postoperative: fasting morning serum cortisol, 24-hour urinary cortisol excretion, serum 11-deoxycortisol after 6 x 750 mg metyrapone. Remission was defined as a fasting morning serum cortisol < 140 nmol/l and/or 24-hour urinary cortisol excretion < 250 nmol. During follow-up: serum cortisol, as well as serum cortisol in the 1 mg overnight dexamethasone-suppression test was measured in order to detect relapse of Cushing's disease. Twelve of 29 patients were not in remission after surgery. These patients all had serum 11-deoxycortisol levels > 350 nmol/l after metyrapone. Seventeen patients met the criteria for early remission. Four of these patients had serum 11-deoxycortisol levels between 150 nmol/l and 350 nmol/l after metyrapone. Three of these 4 patient's experienced a relapse of Cushing's disease during follow-up. In the 13 patients with a serum 11-deoxycortisol < 150 nmol/l after metyrapone, no relapse occurred. The metyrapone test is a useful test in the assessment of outcome of pituitary surgery for Cushing's disease, with a sensitivity of 100% and a specificity of 75% for the early detection of patients at risk of a relapse. Patients in whom a serum 11-deoxycortisol > 150 nmol/L is found after metyrapone are at a high risk for relapse of Cushing's disease.

Pathophysiology of the Neuroregulation of Growth Hormone Secretion in Experimental Animals and the Human

Article

Jan 1999

During the last decade, the GH axis has become the compelling focus of remarkably active and broad-ranging basic and clinical research. Molecular and genetic models, the discovery of human GHRH and its receptor, the cloning of the GHRP receptor, and the clinical availability of recombinant GH and IGF-I have allowed surprisingly rapid advances in our knowledge of the neuroregulation of the GH-IGF-I axis in many pathophysiological contexts. The complexity of the GHRH/somatostatin-GH-IGF-I axis thus commends itself to more formalized modeling (154, 155), since the multivalent feedback-control activities are difficult to assimilate fully on an intuitive scale. Understanding the dynamic neuroendocrine mechanisms that direct the pulsatile secretion of this fundamental growth-promoting and metabolic hormone remains a critical goal, the realization of which is challenged by the exponentially accumulating matrix of experimental and clinical data in this arena. To the above end, we review here the pathophysiology of the GHRH somatostatin-GH-IGF-I feedback axis consisting of corresponding key neurotransmitters, neuromodulators, and metabolic effectors, and their cloned receptors and signaling pathways. We propose that this system is best viewed as a multivalent feedback network that is exquisitely sensitive to an array of neuroregulators and environmental stressors and genetic restraints. Feedback and feedforward mechanisms acting within the intact somatotropic axis mediate homeostatic control throughout the human lifetime and are disrupted in disease. Novel effectors of the GH axis, such as GHRPs, also offer promise as investigative probes and possible therapeutic agents. Further understanding of the mechanisms of GH neuroregulation will likely allow development of progressively more specific molecular and clinical tools for the diagnosis and treatment of various conditions in which GH secretion is regulated abnormally. Thus, we predict that unexpected and enriching insights in the domain of the neuroendocrine pathophysiology of the GH axis are likely be achieved in the succeeding decades of basic and clinical research.

Short-Term Fasting Suppresses Leptin and (Conversely) Activates Disorderly Growth Hormone Secretion in Midluteal Phase Women—A Clinical Research Center Study 1

Article

Mar 1999

Short term fasting activates the corticotropic and somatotropic, and suppresses the reproductive, axis in men. Analogous neuroendocrine responses are less well characterized in women. Recently, we identified a negative association between the adipocyte-derived nutritional signaling peptide, leptin, and pulsatile GH secretion in older fed women. In the present study, we investigated the impact of acute nutrient deprivation on pulsatile GH and LH secretion and mean leptin concentrations in eight healthy young women in the sex-steroid replete milieu of the midluteal phase of the normal menstrual cycle. Volunteers underwent 24-h blood sampling during randomly ordered, short term (2.5-day), fasting vs. fed sessions in separate menstrual cycles. Pulsatile GH and LH secretion over 24 h was quantified by deconvolution analysis, nyctohemeral rhythmicity was quantified by cosinor analysis, and the orderliness of the GH or LH release process was quantified by the approximate entropy statistic. By paired statistical analysis, a 2.5-day fast failed to alter mean (pooled) 24-h serum concentrations of LH, progesterone, estradiol, or PRL, but increased cortisol levels more than 1.5-fold (P = 0.0003). Concurrently, mean (pooled) serum leptin concentrations fell by 75% (P = 0.0003), and insulin-like growth factor I (IGF-I; P < 0.05) and insulin decreased significantly (P = 0.0018). In contrast, the daily pulsatile GH secretion rate rose 3-fold (P < 0.001). Amplified daily GH secretion was attributable mechanistically to a 2.3-fold rise in GH secretory burst mass, reflecting an increased GH secretory burst amplitude (P < 0.01). The GH half-life, duration of GH secretory bursts, and GH pulse frequency did not vary during short term fasting. The disorderliness of GH release increased significantly with nutrient restriction (P = 0.005). The mesor and amplitude of the nyctohemeral serum GH concentration rhythm also rose with fasting (P < 0.01), but the timing of maximal serum GH concentrations did not change. Thus, short-term (2.5-day) fasting during the sex steroid-replete midluteal phase of the menstrual cycle in healthy young women profoundly suppresses 24-h serum leptin and insulin (and to a lesser degree, IGF-I) concentrations, augments cortisol release, but fails to alter daily LH, estradiol, or progesterone concentrations. In contrast, the GH axis exhibits strikingly amplified pulsatile secretion, increased nyctohemeral rhythmicity, and marked disorderliness of the release process. We conclude that the somatotropic axis is more evidently vulnerable to short-term nutrient restriction than the reproductive axis in steroidogenically sufficient midluteal phase women. This study invites the question of whether normal (nutritionally replete) GH secretory dynamics can be restored in fasting women by human leptin, insulin, or IGF-I infusions.

Recent Insights into Neuroendocrine Mechanisms of Aging of the Human Male Hypothalamic‐Pituitary‐Gonadal Axis

Article

Jan 1999

Johannes D. Veldhuis

The concept of the male reproductive axis as an interac- tive and integrated array of regulatory glands, consisting principally of the hypothalamus, anterior pituitary gland (gonadotrope cells), and gonad (seminiferous tubular and Leydig cell compartments), introduces the notion of dy- namic feedback and feedforward control. This concept stands in contrast to the classical perspective of isolating a single gland or cellular ensemble to be studied individ- ually. Here, I review recent insights gained into the aging human (male) gonadotropin-releasing hormone (GnRH)- luteinizing hormone (LH)-testosterone feedback control system. Strategic developments in the quantitation of GnRH-LH neuroregulation in the aging male are updated; namely, monohormonal, bihormonal, multihormonal (LH, FSH, and testosterone), and network (entire axis) control. Lastly, future directions and prominent unresolved issues are discussed with regards to the aging male neuroendo- crine axis. Dynamics and complexity within the male reproductive axis arise, in large part, from the multipartite organization of this feedback control system, with prominent interac- tive regulation operating at molecular, cellular, glandular, and intergiandular levels. For example, critical functional cellular ensembles that operate interactively within and!

Increased episodic release and disorderliness of prolactin secretion in both micro- and macroprolactinomas

Article

Full-text available

Mar 1999

To quantify prolactin (PRL) secretion patterns, ten untreated (female) microprolactinoma patients and six (male) macroprolactinoma patients underwent repetitive blood sampling every 10 min over 24 h. PRL release activity was analyzed from plasma PRL concentration (immunofluorimetric assay) profiles via a model-independent discrete peak detection program (Cluster) and a waveform-independent deconvolution technique (Pulse). Diurnal variations were analyzed by cosinor analysis. The number of distinct PRL pulses (mean +/- S.E.M.) was increased in patients: microprolactinoma 18.6 +/- 0.6/24 h versus female controls 12.4 +/- 0.6 (P = 6.7 x 10-s), and macroprolactinoma 18.0 +/- 0.9 versus male controls 13.5 +/- 0.8/24 h (P = 0.003). In patients, PRL pulse height, amplitude, pulse area and interpeak nadir concentrations were each greatly elevated compared with gender-matched controls. By 2-component deconvolution analysis, the mean nadir PRL secretion rate in microprolactinoma patients was augmented 20-fold at 0.408 +/- 0.089 microgram/l per min versus in female controls 0.019 +/- 0.009 microgram/l per min (P < 0.001); and in macroprolactinoma by 130-fold at 2.067 +/- 0.693 micrograms/l per min versus male controls 0.016 +/- 0.001 microgram/l per min (P = 0.001). Corresponding 24 h mean PRL secretion rates were in women, 0.658 +/- 0.147 and 0.044 +/- 0.018 (P < 0.001), and in men, 3.309 +/- 1.156 and 0.035 +/- 0.010 micrograms/l per min (P = 0.001), being respectively 15- and 94-fold increased in tumors. The estimated PRL production per day was 160 +/- 15 and 187 +/- 20 micrograms in male and female controls respectively. PRL production was 2860 +/- 640 micrograms in female patients with microadenomas (P < 0.001), and 37,800 +/- 5900 micrograms in male macroadenoma patients (P = 0.001). Cosinor analysis of the plasma concentrations revealed a significant rhythm in nine of ten, patients with a microadenoma, and in five of six with a macroadenoma. The same method applied to pulse height and amplitude disclosed a significant rhythm for PRL pulse height, but not for pulse amplitude, suggesting preserved rhythmicity of baseline interpulse nadir PRL concentrations. Approximate entropy (ApEn), a scale- and model-independent regularity statistic, averaged 1.6559 +/- 0.028 in microprolactinoma patients versus 0.8128 +/- 0.079 in female controls (P = 1.7 x 10(-8)); ApEn in macroadenomas was 1.5674 +/- 0.054 versus male controls 0.8773 +/- 0.076 (P = 1.7 x 10(-5), signifying greater secretory irregularity in the patients. Compared with microadenomas, macroadenomas exhibited a higher mean plasma concentration, overall mean PRL secretion rate, nadir secretion rate and pulse area, but similar peak frequency. We conclude that PRL secretion by prolactinomas is characterized by increased plasma PRL episodicity of release, increased total (15- to 100-fold) and basal (20- to 130-fold) secretion rates, and increased disorderlines of minute-to-minute secretion. These abnormalities of secretory control are very similar to those for GH and ACTH identified earlier in acromegaly and Cushing's disease respectively, thus suggesting mechanistic generality of pituitary tumor secretory derangements, independent of the particular hormone.

Tripartite Neuroendocrine Activation of the Human Growth Hormone (GH) Axis in Women by Continuous 24-Hour GH-Releasing Peptide Infusion: Pulsatile, Entropic, and Nyctohemeral Mechanisms 1

Article

Jun 1999

Despite the discovery of potent GH-releasing peptides (GHRPs) more than 15 yr ago and the recent cloning of human, rat, and pig GHRP receptors in the hypothalamus and pituitary gland, the neuroregulatory mechanisms of action of GHRP agonists on the human hypothalamo-somatotroph unit are not well delineated. To gain such clinical insights, we evaluated the ultradian (pulsatile), entropic (pattern orderliness), and nyctohemeral GH secretory responses during continuous 24-h i.v. infusion of saline vs. the most potent clinically available hexapeptide, GHRP-2 (1 microg/kg x h) in estrogen-unreplaced (mean serum estradiol, 12 +/- 2.4 pg/mL) postmenopausal women (n = 7) in a paired, randomized design. Blood was sampled every 10 min for 24 h during infusions and was assayed by ultrasensitive GH chemiluminescence assay. Pulsatile GH secretion was quantitated by deconvolution analysis, orderliness of GH release patterns by the approximate entropy statistic, and 24-h GH rhythmicity by cosinor analysis. Statistical analysis revealed that GHRP-2 elicited a 7.7-fold increase in (24-h) mean serum (+/-SEM) GH concentrations, viz. from 0.32 +/- 0.042 (saline) to 2.4 +/- 0.34 microg/L (GHRP-2; P = 0.0006). This occurred via markedly stimulated pulsatile GH release, namely a 7.1-fold augmentation of GH secretory burst mass: 0.87 +/- 0.18 (control) vs. 6.3 +/- 1.3 microg/L (GHRP-2; P = 0.0038). Enhanced GH pulse mass reflected a commensurate 10-fold (P = 0.023) rise in GH secretory burst amplitude [maximal GH secretory rate (micrograms per L/min) attained within a secretory pulse] with no prolongation in event duration. GH burst frequency, interpulse interval, and calculated GH half-life were all invariant of GHRP-2 treatment. Concurrently, as detected in the ultrasensitive GH assay, GHRP-2 augmented deconvolution-estimated interpulse (basal) GH secretion by 4.5-fold (P = 0.025). The approximate entropy of 24-h serum GH concentration profiles rose significantly during GHRP-2 infusion; i.e. from 0.592 +/- 0.073 (saline) to 0.824 +/- 0.074 (GHRP-2; P = 0.0011), signifying more irregular or disorderly GH release patterns during secretagogue stimulation. Cosinor analysis of 24-h GH rhythms disclosed a significantly earlier (daytime) acrophase at 2138 h (+/- 140 min) during GHRP-2 stimulation vs. 0457 h (+/-42 min) during saline infusion (P = 0.013). Concomitantly, the cosinor amplitude rose 6-fold (P = 0.018), and the mesor (cosine mean) rose 5-fold (P = 0.003). Fasting (0800 h) plasma insulin-like growth factor (IGF-I) concentrations rose by -11 +/- 12 microg/L during saline infusion and by 102 +/- 18 microg/L during GHRP-2 infusion (P = 0.0036). GHRP-2 infusion did not modify (24-h pooled) serum LH, FSH, or TSH concentrations and minimally increased serum (pooled) daily PRL (6.8 +/- 0.83 vs. 12 +/- 1.2 microg/L; P < 0.05) and cortisol (5.3 +/- 0.59 to 7.0 +/- 0.74; P < 0.05) concentrations. In summary, 24-h constant iv GHRP-2 infusion in the gonadoprival female neurophysiologically activates the GH-IGF-I axis by potentiating GH secretory burst mass and amplitude by 7- to 10-fold and augmenting the basal (nonpulsatile) GH secretion by 4.5-fold. GHRP-2 action is highly selective, as it does not alter GH secretory burst frequency, interpulse interval, event duration, or GH half-life. GHRP-2 effectively elevates IGF-I concentrations, unleashes greater disorderliness of GH release patterns, and heightens the 24-h rhythmicity of GH secretion. These tripartite features of GHRP-2's action in estrogen-withdrawn (postmenopausal) women also characterize normal human puberty and/or sex steroid regulation of the GH-IGF-I axis. However, how or whether GHRP-2 interacts further with sex hormone modulation of GH neurosecretory control in older women and men is not yet known.

Disruption of the Young-Adult Synchrony between Luteinizing Hormone Release and Oscillations in Follicle-Stimulating Hormone, Prolactin, and Nocturnal Penile Tumescence (NPT) in Healthy Older Men 1

Article

Nov 1999

The healthy human male hypothalamo-pituitary-gonadal axis exhibits age-dependent loss of coordinate LH-testosterone secretion. A putative independent defect in Leydig-cell steroidogenesis with aging would confound the attribution of such LH-testosterone asynchrony to a hypothalamo-pituitary locus per se. Accordingly, here we appraise by sampling every 2.5 min overnight the joint synchrony of moment-to-moment LH release with simultaneously monitored pituitary FSH secretion, prolactin release, and nocturnal penile tumescence (NPT) oscillations, as a neurophysiological correlate of sleep regulation) in 10 young (ages 21-34) and 8 older (ages 62-72) healthy men. Joint synchrony for paired LH-FSH, LH-prolactin, and LH-NPT observations in young vs. older individuals was quantified by the cross-approximate entropy (cross-ApEn) statistic, with larger cross-ApEn values indicating greater two-variable asynchrony. Concomitantly, we assessed (possible) univariate changes with age for each of LH, FSH, prolactin, and NPT, as quantified by approximate entropy (ApEn). Hormone assays were performed by random-access direct chemiluminescence analyzer. Overnight mean (+/- SEM) serum LH concentrations (IU/L) were equivalent in older (3.1 +/- 0.31 IU/L) and younger (2.9 +/- 0.29) men, as were their serum total testosterone concentrations; viz., 425 +/- 48 (older) and 523 +/- 40 (younger) ng/dL. However, all three sets of paired time-series were significantly more asynchronous in the older cohort. First, cross-ApEn of paired LH-FSH release was significantly higher (or more asynchronous) in older subjects; viz., 1.902 +/- 0.022 in older men vs. 1.607 +/- 0.058 in younger individuals (P = 0.0005). Second, cross-ApEn of paired LH and prolactin release was 1.744 +/- 0.085 in older volunteers vs. 1.346 +/- 0.084 in younger subjects (P = 0.0046). Third, and most notably, cross-ApEn for the joint LH-NPT observation time-series was significantly greater in older subjects at 1.771 +/- 0.056 vs. 1.223 +/- 0.086 (young) (P = 0.0001), thereby denoting loss of coordination between (neural) signals directing intermittent LH secretion and those governing sleep-associated penile tumescence in older men. Among one-variable results, only ApEn of LH release was significantly higher in older individuals at 1.323 +/- 0.058 vs. 0.897 +/- 0.089 in younger subjects (P = 0.0019), signifying greater disorderliness of the LH secretory process in aged men. Individual ApEn values of FSH and prolactin release and NPT were age-invariant. In ensemble, the present clinical experiments indicate that, within the aging male reproductive axis, bihormonal network disruption is more pronounced than individual signal disruption. We suggest that abrogation of joint synchrony among hypothalamically directed pituitary hormones and a neurogenically organized sexual response (nocturnal penile tumescence) can be unified thematically under an hypothesis of disrupted central nervous system hypothalamo-pituitary network coordination in human aging. Such implicit disarray of multinodal communication is of consequence both scientifically and clinically, especially in proposing aging theories and intervention strategies.

A Paradoxical Gender Dissociation within the Growth Hormone/Insulin-Like Growth Factor I Axis during Protracted Critical Illness 1

Article

Feb 2000

Female gender appears to protect against adverse outcome from prolonged critical illness, a condition characterized by blunted and disorderly GH secretion and impaired anabolism. As a sexual dimorphism in the GH secretory pattern of healthy humans and rodents determines gender differences in metabolism, we here compared GH secretion and responsiveness to GH secretagogues in male and female protracted critically ill patients. GH secretion was quantified by deconvolution analysis and approximate entropy estimates of 9-h nocturnal time series in 9 male and 9 female patients matched for age (mean ± sd, 67 ± 11 and 67 ± 15 yr), body mass index, severity and duration of illness, feeding, and medication. Serum concentrations of PRL, TSH, cortisol, and sex steroids were measured concomitantly. Serum levels of GH-binding protein, insulin-like growth factor I (IGF-I), IGF-binding proteins (IGFBPs), and PRL were compared with those of 50 male and 50 female community-living control subjects matched for age and body mass index. In a second study, GH responses to GHRH (1 μg/kg), GH-releasing peptide-2 (GHRP-2; 1 μg/kg) and GHRH plus GHRP-2 (1 and 1 μg/kg) were examined in comparable, carefully matched male (n = 15) and female (n = 15) patients. Despite identical mean serum GH concentrations, total GH output, GH half-life, and number of GH pulses, critically ill men paradoxically presented with less pulsatile (mean ± sd pulsatile GH fraction, 39 ± 14% vs. 67 ± 20%; P = 0.002) and more disorderly (approximate entropy, 0.946 ± 0.113 vs. 0.805 ± 0.147; P = 0.02) GH secretion than women. Serum IGF-I, IGFBP-3, and acid-labile subunit (ALS) levels were low in patients compared with controls, with male patients revealing lower IGF-I (P = 0.01) and ALS (P = 0.005) concentrations than female patients. Correspondingly, circulating IGF-I and ALS levels correlated positively with pulsatile (but not with nonpulsatile) GH secretion. Circulating levels of GH-binding protein and IGFBP-1, -2, and -6 were higher in patients than controls, without a detectable gender difference. In female patients, PRL levels were 3-fold higher, and TSH and cortisol tended to be higher than levels in males. In both genders, estrogen levels were more than 3-fold higher than normal, and testosterone (2.25 ± 1.94 vs. 0.97 ± 0.39 nmol/L; P = 0.03) and dehydroepiandrosterone sulfate concentrations were low. In male patients, low testosterone levels were related to reduced GH pulse amplitude (r = 0.91; P = 0.0008). GH responses to GHRH were relatively low and equal in critically ill men and women (7.3 ± 9.4 vs. 7.8 ± 4.1 μg/L; P = 0.99). GH responses to GHRP-2 in women (93 ± 38 μg/L) were supranormal and higher (P < 0.0001) than those in men (28 ± 16 μg/L). Combining GHRH with GHRP-2 nullified this gender difference (77 ± 58 in men vs. 120 ± 69 μg/L in women; P = 0.4). In conclusion, a paradoxical gender dissociation within the GH/IGF-I axis is evident in protracted critical illness, with men showing greater loss of pulsatility and regularity within the GH secretory pattern than women (despite indistinguishable total GH output) and concomitantly lower IGF-I and ALS levels. Less endogenous GHRH action in severely ill men compared with women, possibly due to profound hypoandrogenism, accompanying loss of the putative endogenous GHRP-like ligand action with prolonged stress in both genders may explain these novel findings.

Growth hormone and prolactin are secreted more irregularly in patients with Cushing's disease

Article

Jun 2000

To investigate whether the spontaneous secretion of growth hormone and prolactin in adult patients with pituitary-dependent Cushing's disease is decreased. Fourteen adult patients (9 women, 5 men; age: 34 +/- 3.4 years, mean +/- SEM) with pituitary-dependent Cushing's disease and 14 controls matched for age, gender and body mass index were studied. Blood samples were withdrawn at 10 minutes intervals starting at 0900 h for 24 h. GH and PRL release were quantified with deconvolution methods. The regularity of GH and PRL release was measured with approximate entropy statistics. The number of GH secretory events per 24 h was higher in patients than in controls: 19 +/- 1.3 vs. 14 +/- 1.5 peaks per 24 h, respectively (P = 0.020). GH secretion rate was about one quarter lower in patients (ns), and the 24 h secretion of PRL was unchanged. Total GH production correlated negatively with the urinary excretion of free cortisol (R = 0.729, P = 0.005) and with the plasma cortisol production rate (R = 0.613; P = 0.026). The orderliness of GH and PRL secretion was appraised with the approximate entropy statistic (ApEn). For GH secretion ApEn(1,20%) in patients was 0.952 +/- 0.084 vs. 0.404 +/- 0.047 in controls, P = 1.17 x 10-4, pointing to a markedly disordered secretion in patients. Similar results were obtained for PRL secretion: patients: 1.586 +/- 0.063 vs. 1.003 +/- 0.068 in controls, P = 3.67 x 10-5. No statistically significant differences in secretory dynamics were demonstrated between the 10 patients with a microadenoma and the four with a macroadenoma. The amount of GH released spontaneously into the circulation in adult patients with pituitary-dependent Cushing's disease is inversely related to the degree of cortisol hypersecretion. However, except for severe hypercortisolism, GH secretion is relatively preserved. In addition, secretion of GH and PRL is remarkably disordered in patients with Cushing's disease. Since we could not detect differences in GH and/or PRL secretory dynamics between patients with a microadenoma and those harboring a macroadenoma, we speculate that an intrapituitary paracrine mechanism and/or elevated cortisol feedback effects may be responsible for the evident disruption of GH and PRL secretion patterns.

Impact of Age on Cortisol Secretory Dynamics Basally and as Driven by Nutrient-Withdrawal Stress*

Article

Jun 2000

The present study tests the clinical hypothesis that aging impairs homeostatic adaptations of cortisol secretion to stress. To this end, we implemented a short-term 3.5-day fast as an ethically acceptable metabolic stressor in eight young (ages 18-35 yr) and eight older (ages 60-72 yr) healthy men. Volunteers were studied in randomly ordered fed vs. fasting sessions. To capture the more complex dynamics of cortisol's feedback control, blood was sampled every 10 min for 24 h for later RIA of serum cortisol concentrations and quantitation of the pulsatile, entropic, and 24-h rhythmic modes of cortisol release using deconvolution analysis, the approximate entropy statistic, and cosine regression, respectively. The stress of fasting elevated the mean (24-h) serum cortisol concentration equivalently in the two age cohorts [i.e. from 7.2 +/- 0.35 to 11.6 +/- 0.71 microg/dL in young men and from 7.7 +/- 0.39 to 12.6 +/- 0.59 microg/dL in older individuals (P < 10(-7))]. The rise in integrated cortisol output was driven mechanistically by selective augmentation of cortisol secretory burst mass (P = 0.002). The resultant daily (pulsatile) cortisol secretion rate increased significantly but equally in young (from 94 +/- 6.3 to 151 +/- 15 microg/dL x day) and older (from 85 +/- 5.4 to 145 +/- 7.3 microg/dL x day) volunteers (P < 10(-4)). Nutrient restriction also prompted a marked reduction in the quantifiable regularity of (univariate) cortisol release patterns in both cohorts (P < 10(-4)). However, older men showed loss of joint synchrony of cortisol and LH secretion even in the fed state, which failed to change with metabolic stress (P < 10(-6)). In addition, older individuals maintained a premature (early-day) cortisol elevation in the fed state and unexpectedly evolved an anomalous further cortisol phase advance of 99 +/- 16 min during fasting (P < 10(-5)). Caloric deprivation in aging men also disproportionately elevated the mesor of 24-h rhythmic cortisol release (P = 10(-7)) and elicited a greater increment in the mean day-night variation in cortisol secretory-burst mass (P < 0.01 vs. young controls). Lastly, short-term caloric depletion in older subjects paradoxically normalized their age-associated suppression of the 24-h rhythm in cortisol interburst intervals. In summary, acute metabolic stress in healthy aging men (compared with young individuals) unmasks distinct, albeit complex, disruption of cortisol homeostasis. These dynamic anomalies impact the feedback-dependent and time-sensitive coupling of pulsatile and 24-h rhythmic cortisol secretion. Nutrient-withdrawal stress in the older male heightens the cortisol phase disparity already evident in fed elderly individuals. Conversely, the stress of fasting in young men paradoxically reproduces selected features of the aging unstressed (fed) cortisol axis; viz., abrogation of joint cortisol-LH synchrony and suppression of the normal diurnal variation in cortisol burst frequency. Whether fasting would unveil analogous disruption of feedback-dependent control of the corticotropic axis in healthy aging women is not yet known.

Gender and Sexual Maturation-Dependent Contrasts in the Neuroregulation of Growth Hormone Secretion in Prepubertal and Late Adolescent Males and Females--A General Clinical Research Center-Based Study

Article

Full-text available

Jul 2000

Although numerous studies have delineated an impact of gender on the neuroendocrine control of GH secretion in the adult, few investigations have defined the nature and extent of sex differences before puberty. This deficit reflects jointly the sensitivity limitations of earlier GH assays and the paucity of intensive sampling protocols in healthy children. Here we have applied a chemiluminescence-based GH assay (sensitivity, 0.005 microg/L) to study GH release in blood sampled every 10 min for 12 h from 1800-0600 h in 58 healthy children. Males and females were evaluated in prepuberty (n = 17 boys; n = 11 girls) and late adolescence (n = 13 males; n = 17 females). We quantitated the principal regulated facets of GH release by 1) deconvolution analysis to assess basal vs. pulsatile GH secretion, 2) approximate entropy to compute the regularity of GH release patterns, and 3) cosine regression analysis to evaluate the overnight rhythmic release of GH. Gender by maturation analysis of variance revealed a mean 2.3-fold increase in the integrated serum GH concentration between prepuberty and late adolescence (P < 10(-6)). Deconvolution analysis disclosed that 91-97% of total GH secretion was pulsatile. Pulsatile, but not basal, GH release showed marked sexual maturation dependence (P < 10(-5)). Pulsatile GH release rose in adolescents due to a 2.25-fold greater GH secretory burst mass (P = 0.00011), which reflected joint 1.5-fold increases in GH secretory pulse amplitude and duration (P < 0.01). Pulse-mass enhancement across puberty was gender independent, but mechanistically specific, as GH pulse frequency, intersecretory burst interval, and half-life were invariant of pubertal status. The approximate entropy statistic identified more disorderly GH secretion patterns in adolescent females compared with prepubertal children and adolescent males (P = 0.00074). Cosinor analysis unmasked elevated overnight rhythms in GH secretory burst mass and interburst intervals in late adolescents of both genders compared with prepubertal boys (for burst mass) or girls (for interburst intervals). Linear regression analysis disclosed strong correlations among 1) the plasma insulin-like growth factor I concentration and GH secretory burst mass (P < 10(-3)), 2) the GH pulse mass and the serum testosterone concentration (P = 10(-3)), 3) the irregularity (entropy) of GH secretory patterns and the serum estradiol concentration (P < 10(-4)), and 4) the basal GH secretion rate and the serum estradiol concentration (P = 10(-2)). In summary, healthy prepubertal children and late adolescent boys and girls manifest distinctive mechanisms controlling GH release, as appraised for all three of the pulsatile, entropic, and 12-h rhythmic modes of GH neuroregulation. The major maturational contrast in the pulsatile mode of GH secretion is amplified secretory burst mass in adolescents due to jointly heightened GH pulse amplitude and duration. The dominant gender distinction lies in the reduced orderliness of GH release patterns in late adolescent girls. Overnight rhythms in GH secretory burst mass and interburst intervals enlarge in both sexes at adolescence, thus signaling enhanced coupling between the rhythmic and pulsatile control of GH release at this time. At the extrema of pubertal development, sex steroid hormones are associated differentially with specific facets of GH release, e.g. an elevated basal GH secretion rate (estrogen), greater irregularity of GH release patterns (estrogen), and amplified GH secretory burst mass and higher plasma insulin-like growth factor I concentrations (testosterone). Accordingly, we postulate that sex steroids supervise selectively each of the dominant facets of GH neurosecretory control across human puberty.

Synergy of L-arginine and growth hormone (GH)-releasing peptide-2 on GH release: Influence of gender

Article

Nov 2000

We test the hypotheses that 1) growth hormone (GH)-releasing peptide-2 (G) synergizes with L-arginine (A), a compound putatively achieving selective somatostatin withdrawal and 2) gender modulates this synergy on GH secretion. To these ends, 18 young healthy volunteers (9 men and 9 early follicular phase women) each received separate morning intravenous infusions of saline (S) or A (30 g over 30 min) or G (1 microg/kg) or both, in randomly assigned order. Blood was sampled at 10-min intervals for later chemiluminescence assay of serum GH concentrations. Analysis of covariance revealed that the preinjection (basal) serum GH concentrations significantly determined secretagogue responsiveness and that sex (P = 0.02) and stimulus type (P < 0.001) determined the slope of this relationship. Nested ANOVA applied to log-transformed measures of GH release showed that gender determines 1) basal rates of GH secretion, 2) the magnitude of the GH secretory response to A, 3) the rapidity of attaining the GH maximum, and 4) the magnitude or fold (but not absolute) elevation in GH secretion above preinjection basal, as driven by the combination of A and G. In contrast, the emergence of the G and A synergy is sex independent. We conclude that gender modulates key facets of basal and A/G-stimulated GH secretion in young adults.

Recent neuroendocrine facets of male reproductive aging

Article

Jan 2001
EXP GERONTOL

J D Veldhuis

We recently identified consistent attenuation of LH and testosterone secretory pulse amplitude and associated disruption of their orderly patterns of release in healthy older men. These dynamic changes emerge despite young-adult concentrations of LH and total testosterone. Moreover, we could document disruption of synchrony between LH secretion and oscillations in FSH, prolactin, sleep-stage and NPT (nocturnal penile tumescence), thus pointing to loss of coordinate neurohormone outflow. Such data suggest that CNS-hypothalamically based regulatory defects may be important in aging, as inferred indirectly in the old male rat and mouse more than 15 years ago. How such alterations are related to specific hypothalamic neurotransmitter changes in aging will be critical to unravel.

Hyperleptinemia in women with Cushing's disease is driven by high-amplitude pulsatile, but orderly and eurhythmic, leptin secretion

Article

Full-text available

Jan 2001

The episodicity of 24 h leptin release was studied in seven women (mean age 39 years, range 22-56 years) with pituitary-dependent hypercortisolism and in seven age- and body mass index (BMI)-matched female controls. Pulsatile leptin release was quantified by model-free cluster analysis and deconvolution, the orderliness of leptin patterns by the approximate entropy statistic (ApEn), and nyctohemeral leptin rhythmicity by cosinor analysis. Blood samples were taken at 10 min intervals for 24 h. Both cluster and deconvolution analysis revealed 2.4-fold increased leptin secretion in patients, caused by combined and equal amplification of basal and pulsatile secretion. Cluster analysis identified 7.1+/-1.5 peaks per 24 h in patients and 6.0+/-0.5 in controls (not significant). The statistical distribution of the individual sample secretory rates was similarly skewed in patients and controls (0.55+/-0.12 vs 0.52+/-0.07). The acrophase (timing of the nyctohemeral leptin peak) in patients occurred at 2314 h (+/-76 min) and at 0058 h (+/-18 min) in controls (not significant). The approximate entropy of leptin release was equivalent in patients and controls (1.67+/-0.03 vs 1.61+/-0.05). The approximate entropy (ApEn) for cortisol in patients was 1.53+/-0.09 and in controls was 0.93+/-0.07 (P<0.0005). Cross-ApEn showed significant pattern synchrony between leptin and cortisol release, which (unexpectedly) was not disrupted by the cortisol excess (patients, 2.02+/-0.04; controls, 1.88+/-0.09; P=0.233). Insulin levels in fasting patients ('fasting insulin') were 27+/-5.7 mU/l vs 14+/-1.6 mU/l in controls (P=0.035). Leptin secretion correlated with fasting insulin levels (R(2)=0.34, P=0.028) and with the cortisol production rate (R(2)=0.33, P=0.033) when patients and controls were combined. In summary, Cushing's disease in women increases leptin production about twofold in an amplitude-specific way. The pulse-generating, nyctohemeral phase-determining, and entropy-control mechanisms that govern the 24 h leptin release are not altered. The increased secretion is not explained by BMI and is probably only partly explained by increased insulin production, suggesting a cortisol-dependent change in adipose leptin secretion.

Growth Hormone (GH) Secretion in Patients with an Inactivating Defect of the GH-Releasing Hormone (GHRH) Receptor Is Pulsatile: Evidence for a Role for Non-GHRH Inputs into the Generation of GH Pulses

Article

Full-text available

Jun 2001

GH secretion is regulated by the interaction of GHRH and somatostatin and is released in 10-20 pulses in each 24-h cycle. The exact roles in pulse generation played by somatostatin, GHRH, and the recently isolated GH-releasing peptide, Ghrelin, are not fully elucidated. To investigate the GHRH-mediated GH secretion in human, we investigated pulsatile, entropic, and 24-h rhythmic GH secretion in two young adults (male, 24 yr; female, 23 yr) from a Moroccan family with a novel inactivating defect of the GHRH receptor gene. Data were compared with values in age- and gender-matched controls. Plasma GH concentration were measured by a sensitive immunofluorometric assay, with a detection limit of 0.01 mU/L. All plasma GH concentrations in the female patient were measurable; in the male patient 30 of 145 samples were at or below the detection limit. GH secretion was pulsatile, with 21 and 23 secretory episodes/24 h in the male and female patients, respectively. The fraction of basal to total GH secretion was raised in both patients by 0.18 and 0.15, respectively. The total 24-h GH production rate was greatly diminished; in the male patient it was 6.9 mU/L (normal values for his age, 26--63 mU/L), and in the female patient it was 4.2 mU/L (normal values for her age, 96--390 mU/L). The nyctohemeral plasma GH rhythm was preserved (P < 0.001), with normal acrophases (0430 and 0218 h in the male and female, respectively). Approximate entropy was greatly elevated in both subjects (0.82 in the male and 1.17 in the female; upper normal values for age and gender, 0.24 and 0.59, respectively). Intravenous injection of 50 microg GHRH failed to increase the plasma GH concentration in both patients, but 100 microg GH-releasing peptide-2 elicited a definite increase (male patient, 0.13 to 1.74 mU/L; female patient, 0.29 to 0.87 mU/L). Both patients had a partial empty sella on magnetic resonance imaging scanning. In summary, the present studies in two patients with a profound loss of function mutation of the GHRH receptor favor the view that in the human the timing of GH pulses is primarily supervised by intermittent somatostatin withdrawal, and the amplitude of GH pulses is driven by GHRH. In addition, we infer that effectual GHRH input controls the GH cell mass and the orderliness of the secretory process.

Nonlinear Dynamics and Chaos Theory: Concepts and Applications Relevant to Pharmacodynamics

Article

May 2001

The theory of nonlinear dynamical systems (chaos theory), which deals with deterministic systems that exhibit a complicated, apparently random-looking behavior, has formed an interdisciplinary area of research and has affected almost every field of science in the last 20 years. Life sciences are one of the most applicable areas for the ideas of chaos because of the complexity of biological systems. It is widely appreciated that chaotic behavior dominates physiological systems. This is suggested by experimental studies and has also been encouraged by very successful modeling. Pharmacodynamics are very tightly associated with complex physiological processes, and the implications of this relation demand that the new approach of nonlinear dynamics should be adopted in greater extent in pharmacodynamic studies. This is necessary not only for the sake of more detailed study, but mainly because nonlinear dynamics suggest a whole new rationale, fundamentally different from the classic approach. In this work the basic principles of dynamical systems are presented and applications of nonlinear dynamics in topics relevant to drug research and especially to pharmacodynamics are reviewed. Special attention is focused on three major fields of physiological systems with great importance in pharmacotherapy, namely cardiovascular, central nervous, and endocrine systems, where tools and concepts from nonlinear dynamics have been applied.

Corticotropin Secretory Dynamics in Humans under Low Glucocorticoid Feedback

Article

Nov 2001

To explore the mechanisms of homeostatic adaptation of the hypothalamo-pituitary-adrenal axis to an experimental low-feedback condition, we quantitated pulsatile (ultradian), entropic (pattern-sensitive), and 24-h rhythmic (circadian) ACTH secretion during high-dose metyrapone blockade (2 g orally every 2 h for 12 h, and then 1 g every 2 h for 12 h). Plasma ACTH and cortisol concentrations were sampled concurrently every 10 min for 24 h in nine adults. The metyrapone regimen reduced the amplitude of nyctohemeral cortisol rhythm by 45% (P = 0.0013) and delayed the time of the cortisol maximum (acrophase) by 7.1 h (P = 0.0002). Attenuated cortisol negative feedback stimulated a 7-fold increase in the mean (24-h) plasma ACTH concentration, which rose from 24 +/- 1.6 to 169 +/- 31 pg/ml (ng/liter) (P < 0.0001). Augmented ACTH output was driven by a 12-fold amplification of ACTH secretory burst mass (integral of the underlying secretory pulse) (21 +/- 3.1 to 255 +/- 64 pg/ml; P < 0.0001), yielding a higher percentage of ACTH secreted in pulses (53 +/- 3.5 vs. 92 +/- 1.3%; P < 0.0001). There were minimal elevations in basal (nonpulsatile) ACTH secretion (by 50%; P = 0.0049) and ACTH secretory burst frequency (by 36%; P = 0.031). The estimated half-life of ACTH (median, 22 min) and the calculated ACTH secretory burst half-duration (pulse event duration at half-maximal amplitude) (median, 23 min) did not change. Hypocortisolemia evoked remarkably more orderly subordinate patterns of serial ACTH release, as quantitated by the approximate entropy statistic (P = 0.003). This finding was explained by enhanced regularity of successive ACTH secretory pulse mass values (P = 0.032). In contrast, there was no alteration in serial ACTH interpulse-interval (waiting-time) regularity. At the level of 24-h ACTH rhythmicity, cortisol withdrawal enhanced the daily rhythm in ACTH secretory burst mass by 29-fold, elevated the mesor by 16-fold, and delayed the acrophase by 3.4 h from 0831 h to 1154 h (each P < 10(-3)). In summary, short-term glucocorticoid feedback deprivation primarily (>97% of effect) amplifies pulsatile ACTH secretory burst mass, while minimally elevating basal/nonpulsatile ACTH secretion and ACTH pulse frequency. Reduced cortisol feedback paradoxically elicits more orderly (less entropic) patterns of ACTH release due to emergence of more regular ACTH pulse mass sequences. Cortisol withdrawal concurrently heightens the amplitude and mesor of 24-h rhythmic ACTH release and delays the timing of the ACTH acrophase. In contrast, the duration of underlying ACTH secretory episodes is not affected, which indicates that normal pulse termination may be programmed centrally rather than imposed by rapid negative feedback. Accordingly, we hypothesize that adrenal glucocorticoid negative feedback controls hypothalamo-pituitary-adrenal axis dynamics via the 3-fold distinct mechanisms of repressing the mass of ACTH secretory bursts, reducing the orderliness of the corticotrope release process, and modulating the intrinsic diurnal rhythmicity of the hypothalamo-corticotrope unit.

Mechanisms of Hypothalamic-Pituitary-Gonadal Disruption in Polycystic Ovarian Syndrome

Article

Nov 2001
ARCH MED RES

Although the pathogenesis of polycystic ovarian syndrome (PCOS) is still controversial, a series of investigations has demonstrated an array of neuroendocrine abnormalities as a major component of the syndrome. From a neuroendocrine perspective, patients with PCOS exhibit an accelerated frequency and/or higher amplitude of LH pulses, augmentation of LH secretory burst mass, and a more disorderly LH release. Elevated in vitro LH bioactivity and a preponderance of basic LH isoforms, which correlate positively with elevated serum 17-hydroxyprogesterone, androstenedione, and testosterone concentrations, also characterize adolescents with PCOS. Heightened GnRH drive of gonadotropin secretion and a steroid-permissive milieu appear to jointly promote elevated secretion of basic LH isoforms. Positive feedback is implied, because hypersecretion of highly bioactive LH in PCOS probably contributes to inordinate androgen output. However, the precise nature of feedback disruption remains uncertain. Indeed, recent data suggest that PCOS is marked by anomalies of both feedforward and feedback signaling between GnRH/LH and ovarian androgens. From a single hormone perspective, the individual patterns of LH and androstenedione release are consistently more irregular in patients with PCOS. Bihormonal analysis has disclosed concomitant uncoupling of the pairwise synchrony of LH and testosterone, LH and androstenedione, and testosterone and androstenedione secretion. The foregoing ensemble of findings points to deterioration of both orderly uniglandular and coordinate bihormonal output in PCOS. Additional studies are needed to establish the primary pathophysiologic mechanisms underlying this disorder.

Impact of Estradiol Supplementation on Dual Peptidyl Drive of GH Secretion in Postmenopausal Women

Article

Mar 2002

As an indirect probe of estrogen-regulated hypothalamic somatostatin restraint, the present study monitors the ability of short-term oral E2 supplementation to modulate GH secretion during combined continuous stimulation by recombinant human GHRH [GHRH-(1-44)-amide] and the potent and selective synthetic GH-releasing peptide, GHRP-2. According to a simplified tripeptidyl model of GH neuroregulation, the effects of estrogen in this dual secretagogue paradigm should mirror alterations in endogenous somatostatinergic signaling. To this end, seven healthy postmenopausal women underwent frequent (10-min) blood sampling for 24 h during simultaneous i.v. infusion of GHRH and GHRP-2 each at a rate of 1 microg/kg x h on d 10 of randomly ordered placebo or 17beta-estradiol (E2) (1 mg orally twice daily) replacement. Serum GH concentrations (n = 280/subject) were assayed by chemiluminescence. The resultant GH time series was evaluated by deconvolution analysis, the approximate entropy statistic, and cosine regression to quantitate pulsatile, entropic (feedback-sensitive), and 24-h rhythmic GH release, respectively. Statistical comparisons revealed that E2 repletion increased the mean (+/- SEM) serum E2 concentration to 222 +/- 26 pg/ml from 16 +/- 1.7 pg/ml during placebo (P < 0.001) and suppressed the serum LH by 48% (P = 0.0033), serum FSH by 64% (P < 0.001), and serum IGF-I by 44% (P = 0.021). Double peptidyl secretagogue stimulation elevated mean 24-h serum GH concentrations to 8.1 +/- 1.0 microg/liter (placebo) and 7.7 +/- 0.89 microg/liter (E2; P = NS) and evoked prominently pulsatile patterns of GH secretion. No primary measure of pulsatile or basal GH release was altered by the disparate sex steroid milieu, i.e. GH secretory burst amplitudes of 0.62 +/- 0.93 (placebo) and 0.72 +/- 0.16 (E2) microg/liter x min, GH pulse frequencies of 27 +/- 1.8 (placebo) and 23 +/- 1.9 (E2) events/24 h, GH half-lives of 12 +/- 0.74 (placebo) and 15 +/- 4.5 (E2) min, and basal (nonpulsatile) GH secretion 70 +/- 22 (placebo) and 57 +/- 18 (E2) ng/liter x min. The approximate entropy (ApEn) of serial GH release [1.297 +/- 0.061 (placebo) and 1.323 +/- 0.06 (E2)] and the mesor (cosine mean), amplitude, and acrophase (time of the maximum) of 24-h rhythmic GH secretion were likewise invariant of estrogen supplementation. Estimated statistical power exceeded 90% for detecting significant (P < 0.05) within-subject changes exceeding 30-50% in the mean serum GH concentration, GH ApEn, or GH mesor. In contrast, ApEn analysis of the evolution of successive GH secretory burst-mass values over 24 h disclosed that E2 replacement disrupts the serial regularity of pulsatile GH output (elevates the ApEn ratio) during combined GHRH/GHRP-2 stimulation (P = 0.004). In summary, short-term elevation of serum E2 concentrations in postmenopausal individuals into the midfollicular phase range observed in young women does not significantly alter 24-h basal, pulsatile, entropic, or nyctohemeral GH secretion monitored under continuous combined drive by GHRH and GHRP-2. As E2 repletion without enforced GHRH/GHRP-2 stimulation augments each of the foregoing regulated facets of GH release, we infer that one or both of the infused peptidyl secretagogues may itself participate in E2's short-term amplification of GH secretion in postmenopausal individuals. Estrogen's disruption of the orderliness of sequential GH pulse-mass values during fixed GHRH/GHRP-2 feedforward would be consistent with a subtle reduction in the release and/or actions of hypothalamic somatostatin or an (unexpected) direct pituitary action of the sex steroid. Whether comparable dynamics mediate the effects of endogenous estrogen on the GH axis in premenopausal women or pubertal girls is not known.

Unequal Impact of Short-Term Testosterone Repletion on the Somatotropic Axis of Young and Older Men

Article

Mar 2002

The present clinical study compares the impact of low- and high-dose parenteral testosterone (T) supplementation on daily GH secretory patterns and serum IGF-I, IGFBP-1, and IGFBP-3 concentrations in healthy older (60-82 yr) and young (20-40 yr) men. To this end, we administered three consecutive weekly injections of randomly ordered saline and either a low (100 mg) or a high (200 mg) dose of testosterone enanthate im; namely, saline (n = 17, young and n = 16, older), a low dose (n = 8 young, n = 8 older) and a high dose (n = 9 young, and n = 8 older) of androgen. To monitor somatotropic-axis responses, blood was sampled every 10 min for 24 h for later chemiluminescence-based assay of serum GH, RIA of serum IGF-I, and immunoradiometric assay of serum IGFBP-1 and IGFBP-3 concentrations. Data were analyzed via a nested analysis of covariance statistical design. At baseline (saline injection), older, compared with young, men maintained: 1) similar serum total T, IGFBP-1, and IGFBP-3 but reduced IGF-I concentrations, namely, mean (+/- SEM) IGF-I 160 plus or minus 15 vs. 280 plus or minus 18 microg/liter, (P < 0.001); 2) reduced GH secretory burst mass (0.68 +/- 0.09 vs. 1.2 +/- 0.20 microg/liter, P = 0.031); 3) more disorderly GH release patterns (approximate entropy 0.501 +/- 0.058 vs. 0.288 +/- 0.021, P < 0.001); and 4) blunted 24-h rhythmic GH output (nyctohemeral amplitude 0.25 +/- 0.05 vs. 0.47 +/- 0.08 microg/liter, P = 0.025). Serum T concentrations (ng/dl) did not differ in the two age groups supplemented with either a low dose [550 +/- 50 (young) and 544 +/- 128 (older)] and high [1320 +/- 92 (young) and 1570 +/- 140 (older)] dose of T. The 100-mg dose of androgen exerted no detectable effect on GH secretion in either age cohort but increased the serum IGF-I concentration in young men by 20% (P = 0.00098). The 200-mg dose of T failed to alter daily GH production in young volunteers but in older men stimulated: 1) a 2.03-fold rise in the mean (24-h) serum GH concentration (P = 0.0053, compared with the response to saline); 2) a 1.20-fold increase in basal (nonpulsatile) GH production (P = 0.039); 3) a 2.15-fold amplification of GH secretory burst mass (P = 0.0020); 4) a 2.17-fold elevation of the Mesor of nyctohemeral GH output (P = 0.025); 5) a 1.79-fold enhancement in GH approximate entropy (P = 0.0003); and 6) a 40% increase in the fasting serum IGF-I concentration (P = 0.000005). Multivariate statistical analysis indicated that following high-dose T administration, the E2 increment significantly predicted the IGF-I increment in both age groups combined (P = 0.003); T dose positively forecast the serum total IGF-I concentration (P = 0.0031); and age and T dose jointly determined serum LH concentrations (P = 0.031). In summary, neither a physiological nor a pharmacological dose of T administered parenterally for 3 wk augments daily GH secretion in eugonadal young men. In contrast, a high dose of aromatizable androgen significantly amplifies 24-h basal, pulsatile, entropic, and nyctohemerally rhythmic GH production and elevates the serum IGF-I concentration in older men. The mechanistic basis for the foregoing age-related distinction in GH/IGF-I axis responsivity to T is not known.

Pulsatile, nyctohemeral and entropic characteristics of GH secretion in adult GH-deficient patients: Selectively decreased pulsatile release and increased secretory disorderliness with preservation of diurnal timing and gender distinctions

Article

Jan 2002

The present clinical investigation uses a high-precision GH immunofluorometric assay to examine the postulate that principally the amplitude mode of GH secretory control is disrupted in adults with GH deficiency. To this end, we investigated GH secretory dynamics in a cohort of 19 adult GH-deficient (GHD) patients and 19 age-, gender- and body mass index-matched controls. GHD was established by blunted (< 7 mU/l) GH release during insulin-induced hypoglycaemia. Twenty-four-hour serum GH concentration profiles obtained by 10-min sampling were analysed by deconvolution, cosinor analysis and approximate entropy to appraise pulsatile, diurnally rhythmic, and pattern-dependent GH secretion, respectively. Deconvolution analysis revealed that pulsatile GH release was decreased by threefold, due to amplitude-specific damping, detectable GH secretory burst frequency was paradoxically increased by twofold, but basal non-pulsatile GH release was fully preserved. GH half-life in patients and controls was similar, thus excluding major kinetic differences. The acrophase (time of maximum) of the 24-h GH rhythm was unchanged. The regularity of the GH release process, as measured by ApEn, was decreased profoundly in GHD patients (P < 10(-8)). The changes in GH secretion were similar in irradiated and nonirradiated patients. Daily GH secretion was also comparable in male and female GHD patients, but plasma IGF-I concentrations were higher in male than female patients (P = 0.031). Furthermore, the gender-specific GH ApEn difference, evident in controls, was still demonstrable in patients (P = 0.017). The ratio of plasma IGF-I and pulsatile GH production was increased threefold in patients (P = 0.004), pointing to increased sensitivity to GH in GH deficiency and/or non-GH-dependent IGF-I production. The present detailed analyses of daily GH secretory dynamics in patients with (moderate) GH deficiency document an amplitude-specific decrease in pulsatile GH secretion, which is partly compensated for by increased GH pulse frequency. The remarkably disorderly patterns of GH secretion in patients identify other major alterations in GH neuroregulation in such individuals, reflecting withdrawal of expected GH and/or IGF-I repression of pulsatile GH secretion. Preservation of the nyctohemeral timing of GH release and the gender contrast in GH ApEn in GHD patients would also be consistent with partial retention of central neuroregulation and GH/IGF-I feedback-dependent control in hypopituitary subjects.

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

Article

Full-text available

Feb 1998

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 microg/l), and the normalization of the paradoxical rise of GH to TRH or GnRH. In patients with active acromegaly ApEn was 1.23+/-0.04, with no overlap with the control subjects (P = 1.2 x 10[-16]), who had an ApEn of 0.40+/-0.04. ApEn in patients shortly after surgery was 0.71+/-0.09 (P < 0.001 vs controls), and long after surgery 0.56+/-0.05 (P < 0.011 vs controls). ApEn values in treated and untreated patients correlated significantly with the plasma concentration of IGF-I (r=0.531) and IGFBP-3 (r=0.598), and the log-transformed 24h GH secretion rate (r=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.

Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay

Article

Full-text available

Dec 1995

A chemiluminescence-based GH assay with 30- to 100-fold increased sensitivity recently disclosed combined basal and pulsatile GH secretion in men. However, how age, sex steroid hormones, and obesity singly and jointly influence the basal vs. pulsatile modes of GH release is not known. We used the foregoing assay (detection threshold, 0.002-0.005 microgram/L) and high sensitivity and specificity (> or = 90% each) deconvolution analysis to quantitate basal and pulsatile GH secretion from 24-h serum GH concentration profiles in 26 healthy lean and obese men, whose ages spanned 18-63 yr and whose percentage body fat ranged from 12-47%. Concentrations of serum insulin-like growth factor I (IGF-I), IGF-I-binding protein-1 (IGFBP-1), and IGFBP-3 were related to specific measures of basal or pulsatile GH release. We observed that mean (24-h) serum GH concentrations embraced a 140-fold range from 0.013-1.8 micrograms/L and were related negatively to age (r = -0.50; P < 0.01), percentage body fat (r = -0.620; P < 0.01), and their interaction (r = -0.610; P < 0.01). In contrast, testosterone was a robustly positive statistical determinant of mean serum GH values (r = 0.628; P = 0.0006). Stepwise multivariate regression analysis disclosed that percentage body fat alone and jointly with the serum testosterone concentration controlled, respectively, 38% and 50% of the total variability in GH levels (P = 0.0013 and P = 0.0008). As assessed by deconvolution analysis, GH secretory burst mass was negatively related to percentage body fat (r = -0.621; P < 0.01) and positively to serum testosterone (r = 0.529; P = 0.0054). The calculated half-life of GH correlated positively with serum estradiol (r = 0.447; P = 0.032), and negatively with percentage body fat (r = -0.437; P = 0.048). Basal GH secretion rates were negatively related to serum estradiol (r = -0.485; P = 0.016). In contrast, GH secretory burst frequency and duration were unrelated to age, percentage body fat, or sex steroids. The fraction of total GH secreted in bursts was negatively correlated with the body mass index (r = -0.540; P < 0.01). Serum IGF-I concentrations were positively related to total pulsatile GH secretion (r = 0.690; P = 0.0011) and negatively to age (r = -0.597; P = 0.007) and percentage body fat (r = -0.611; P = 0.009).(ABSTRACT TRUNCATED AT 400 WORDS)

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

Article

Full-text available

Sep 1994

Pulses of growth hormone (GH) release in acromegaly may arise from hypothalamic regulation or from random events intrinsic to adenomatous tissue. To distinguish between these possibilities, serum GH concentrations were measured at 5-min intervals for 24 h in acromegalic men and women with active (n = 19) and inactive (n = 9) disease and in normal young adults in the fed (n = 20) and fasted (n = 16) states. Daily GH secretion rates, calculated by deconvolution analysis, were greater in patients with active acromegaly than in fed (P < 0.05) but not fasted normal subjects. Significant basal (nonpulsatile) GH secretion was present in virtually all active acromegalics but not those in remission or in fed and fasted normal subjects. A recently introduced scale- and model-independent statistic, approximate entropy (ApEn), was used to test for regularity (orderliness) in the GH data. All but one acromegalic had ApEn values greater than the absolute range in normal subjects, indicating reduced orderliness of GH release; ApEn distinguished acromegalic from normal GH secretion (fed, P < 10(-12); fasted, P < 10(-7)) with high sensitivity (95%) and specificity (100%). Acromegalics in remission had ApEn scores larger than those of normal subjects (P < 0.0001) but smaller than those of active acromegalics (P < 0.001). The coefficient of variation of successive incremental changes in GH concentrations was significantly lower in acromegalics than in normal subjects (P < 0.001). Fourier analysis in acromegalics revealed reduced fractional amplitudes compared to normal subjects (P < 0.05). We conclude that GH secretion in acromegaly is highly irregular with disorderly release accompanying significant basal secretion.

Maturation of the Regulation of Growth Hormone Secretion in Young Males with Hypogonadotropic Hypogonadism Pharmacologically Exposed to Progressive Increments in Serum Testosterone 1

Article

Full-text available

May 1997

To study the onset of the action of gonadal sex steroids on the GH axis in spontaneous puberty, which is prolonged and sparingly predictable, we present a clinical investigative paradigm in which six previously untreated boys with isolated hypogonadotropic hypogonadism were exposed to progressively higher testosterone levels designed to mimic the androgen environment recognized during the early stages of puberty. We administered three incremental doses of testosterone (25-, 50-, and 100-mg im injections), each over a period of 4 weeks. Studies of overnight pulsatile GH secretion and GH responses to GHRH alone or combined with L-arginine (a functional somatostatin antagonist) were performed before testosterone administration and after each dose of testosterone. Serum testosterone, but not estrogen, levels increased progressively in all subjects during therapy. Deconvolution analysis of GH release profiles disclosed that GH secretory burst mass was stimulated significantly even by 25 mg testosterone. This parameter was not altered further by higher doses of testosterone. Spontaneous GH secretory burst number and amplitude increased significantly only after the 50- and 100-mg testosterone treatments, after which the serum GH response to GHRH and arginine also rose significantly. In contrast, the GH response to GHRH alone was not significantly affected by any dose of testosterone. Serum testosterone levels correlated significantly with the primary parameters of nocturnal GH secretion. In summary, our experimental model suggests that in males even very small increases in circulating testosterone occurring during the earliest stages of puberty are able to amplify pulsatile GH secretion. Our concomitant secretagogue data further suggest that testosterone exerts its action at different sites in the hypothalamo-somatotropic axis, i.e. directly at the pituitary level, and also at hypothalamic loci, possibly increasing both GHRH and somatostatin release.

Pyridostigmine treatment selectively amplifies the mass of GH secreted per burst without altering GH burst frequency, half-life, basal GH secretion or the orderliness of GH release

Article

Full-text available

Oct 1997

Growth hormone (GH) release from the anterior pituitary gland is predominantly regulated by the two antagonistic hypothalamic peptides, growth hormone-releasing hormone (GHRH) and somatostatin. Appraising endogenous GHRH action is thus made difficult by the confounding effects of (variable) hypothalamic somatostatin inhibitory tone. Accordingly, to evaluate endogenous GHRH actions, we used a clinical model of presumptively acute endogenous somatostatin withdrawal with concomitant GHRH release. To this end, we administered in randomized order placebo or the indirect cholinergic agonist, pyridostigmine, for 48 h to 13 healthy men of varying ages (29-77 years) and body mass indices (21-47 kg/m2). We sampled blood at 10-min intervals for 48 h during both placebo and pyridostigmine (60 mg orally every 6 h) administration, and used an ultrasensitive GH chemiluminescence assay (sensitivity 0.0002-0.005 microgram/l) to capture GH pulse profiles. Multiparameter deconvolution analysis was applied to quantitate the number, amplitude, mass, and duration of significant underlying GH secretory bursts, and simultaneously estimate the GH half-life and concurrent basal GH secretion. Approximate entropy was utilized as a novel regularity statistic to quantify the relative orderliness of the hormone release process. All measures of GH secretion/half-life and orderliness were statistically invariant across the two consecutive 24-h placebo sessions. In contrast, pyridostigmine treatment significantly increased the mean serum GH concentration from 0.23 +/- 0.054 microgram/l during placebo to 0.45 +/- 0.072 microgram/l during the first day of treatment (P < 0.01). There was also a significant rise in the calculated 24-h pulsatile GH production rate from 8.9 +/- 1.7 micrograms/l/day on placebo to 27 +/- 5.6 micrograms/l/day during active drug treatment (P < 0.01). Pyridostigmine significantly and selectively amplified GH secretory burst mass to 1.5 +/- 0.35 micrograms/l compared with 0.74 +/- 0.19 microgram/l on placebo (P < 0.01). This was attributable to stimulation of GH secretory burst amplitude (maximal rate of GH secretion attained within the release episode) with no prolongation of estimated burst duration. Basal GH secretion and approximate entropy were not altered by pyridostigmine. However, age was strongly related to more disorderly GH release during both days of pyridostigmine treatment (r = +0.79, P = 0.0013). During the second 24-h of continued pyridostigmine treatment, most GH secretory parameters decreased by 15-50%, but in several instances remained significantly elevated above placebo. Body mass index, but not age, was a significantly negative correlate of the pyridostigmine-stimulated increase in GH secretion (r = -0.65, P = 0.017). In summary, assuming that somatostatin is withdrawn and (rebound) GHRH release is stimulated via pyridostigmine administration, we infer that relatively unopposed GHRH action principally controls GH secretory burst mass and amplitude, rather than apparent GH secretory pulse duration, the basal GH secretion rate, or the serial regularity/orderliness of the GH release process in the human. Moreover, we infer that increasing age is accompanied by greater disorderliness of somatostatin-withdrawn GHRH, and hence rebound GH, release. The strongly negative correlation between pyridostigmine-stimulated GH secretion and body mass index (but not age) further indicates that increased relative adiposity may result in decreased effective (somatostatin-withdrawn) endogenous GHRH stimulus strength.

Increased Disorderliness of Basal Insulin Release, Attenuated Insulin Secretory Burst Mass, and Reduced Ultradian Rhythmicity of Insulin Secretion in Older Individuals 1

Article

Full-text available

Dec 1997

Insulin is secreted in a pulsatile fashion. Rapid pulses are considered to be important for inhibiting hepatic glucose output, and ultradian pulses for stimulating peripheral glucose disposal. Aging is characterized by a progressive impairment in carbohydrate tolerance. We undertook the current studies to determine whether alterations in pulsatile insulin release accompany the age-related changes in carbohydrate metabolism. Healthy young (n = 8; body mass index, 21 ± 1 kg/m2; age, 24 ± 1 yr) and old (n = 9; body mass index, 24 ± 1 kg/m2; age, 77 ± 2 yr) volunteers underwent two studies. In the first study, insulin was sampled every 1 min for 150 min, and pulse analysis was conducted using a recently validated multiparameter deconvolution technique. In the second study, insulin was sampled every 10 min for 600 min, and insulin release was evaluated by Cluster analysis. In the 150-min studies, insulin secretory burst mass (P < 0.05) and amplitude (P < 0.01) were reduced in the elderly. In addition, approximate entropy, a measure of irregularity or disorderliness of insulin release, was increased in the aged (P < 0.01). In the 600-min studies, interpulse interval was greater in the aged (P < 0.05), and burst number was less (P < 0.05). We conclude that normal aging is characterized by more disorderly insulin release, a reduction in the amplitude and mass of rapid insulin pulses, and a decreased frequency of ultradian pulses. Whether these alterations in insulin pulsatility contribute directly to the age-related changes in carbohydrate metabolism will require further study.

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

Article

Full-text available

Aug 1998
Am J Physiol

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.

Approximate Entropy as a Measure of System Complexity

Article

Full-text available

Apr 1991

Steve Pincus

Techniques to determine changing system complexity from data are evaluated. Convergence of a frequently used correlation dimension algorithm to a finite value does not necessarily imply an underlying deterministic model or chaos. Analysis of a recently developed family of formulas and statistics, approximate entropy (ApEn), suggests that ApEn can classify complex systems, given at least 1000 data values in diverse settings that include both deterministic chaotic and stochastic processes. The capability to discern changing complexity from such a relatively small amount of data holds promise for applications of ApEn in a variety of contexts.

Differential orderliness of the GH release process in castrate male and female rats

Article

Feb 1998

Male- and female-specific modes of episodic growth hormone (GH) release are presumptively imposed by sex steroid hormones, and, although typically evident visually, are vividly distinguished quantitatively via a regularity statistic, approximate entropy (ApEn), in both the rat and human. GH secretory patterns may determine GH-stimulated growth and specific hepatic and muscle gene expression in the rat. Consequently, it is important to discern mechanisms that underlie their regulation. Here we have examined the impact of prepubertal gonadal suppression (at 4 wk of age) via surgical or pharmacological [gonadotropin-releasing hormone (GnRH) agonist] intervention on the regularity (ApEn) of GH release in male and female rats (at 10-11 wk of age) sampled at 10-min intervals for 10 h (n = 60 points) during a lights-out (dark) period. We observed a graded hierarchy of mean disorderliness of GH release that was quantifiable by ApEn measures, with maximal to minimal disorderliness in the following rank order: intact female, GnRH agonist-treated female, ovariectomized female, orchidectomized male, GnRH agonist-treated male, and intact male. These observations suggest a continuum of sex steroid actions on the regularity of GH secretion and, by inference, on the interplay among GH-releasing hormone, somatostatin, and GH/insulin-like growth factor I negative feedback.

Maturation of the Regulation of Growth Hormone Secretion in Young Males with Hypogonadotropic Hypogonadism Pharmacologically Exposed to Progressive Increments in Serum Testosterone

Article

Apr 1997

A Giustina

Estrogen and Testosterone, But Not a Nonaromatizable Androgen, Direct Network Integration of the Hypothalamo-Somatotrope (Growth Hormone)-Insulin-Like Growth Factor I Axis in the Human: Evidence from Pubertal Pathophysiology and Sex-Steroid Hormone Replacement

Article

Oct 1997

J. D. Veldhuis

Increased Disorderliness of Basal Insulin Release, Attenuated Insulin Secretory Burst Mass, and Reduced Ultradian Rhythmicity of Insulin Secretion in Older Individuals

Article

Dec 1997

G. S. Meneilly

Prolonged Half Live of LH in Adolescents with Polycystic Ovary Syndrome (PCO): Assessment by Deconvolution Analysis

Article

Mar 1999

Twenty-Four-Hour Rhythms in Plasma Concentrations of Adenohypophyseal Hormones Are Generated by Distinct Amplitude and/or Frequency Modulation of Underlying Pituitary Secretory Bursts*

Article

Jan 1991

To evaluate the nature of anterior pituitary secretory events in vivo, we have applied a novel waveform-independent deconvolution technique that dissects the underlying secretory behavior of endocrine glands quantitatively from available serial plasma hormone concentration measurements assuming one- or two-compartment elimination kinetics. We used this new tool to ask the following physiological questions. 1) Does the pituitary gland secrete exclusively in randomly dispersed bursts, and/or does a tonic (constitutive) mode of interburst hormone secretion exist? 2) What secretory mechanisms generate the nyctohemeral rhythms in plasma hormone concentrations? Analysis of 24-h plasma concentration profiles of GH, LH, FSH, PRL, TSH, ACTH, and beta-endorphin (n = 6-8 men/group) revealed that 1) pituitary secretion in vivo occurs in an exclusively burst-like mode for all hormones except TSH and PRL (for the latter two, a mixed burst and constitutive mode pertained); 2) significant nyctohemeral regulation of secretory burst frequency alone was not demonstrated for any hormone; 3) prominent 24-h variations in secretory burst amplitude alone were delineated for ACTH and LH; 4) TSH, GH, and beta-endorphin were both frequency and amplitude controlled; 5) no significant diurnal variations in FSH secretory parameters occurred; and 6) a fixed hormone half-life yielded fits of the 24-h data series with a normalized residual variance of less than 8%. We conclude that the normal human anterior pituitary gland releases its multiple (glyco)protein hormones via punctuated secretory episodes unassociated with tonic basal (constitutive) hormone secretion, except in the case of TSH and PRL. Hormone-specific amplitude and/or frequency control of secretory burst activity over 24 h provides the mechanistic basis for the classically recognized 24-h rhythms in plasma concentrations of adenohypophyseal hormones in men.

Increased disorderliness and amplified basal and pulsatile aldosterone secretion in patients with primary aldosteronism

Article

Jan 1995

To investigate the pathophysiology of altered aldosterone secretion in patients with primary aldosteronism, the pulsatile mode of in vivo aldosterone and cortisol release was examined by quantitative deconvolution analysis in 5 normal subjects (controls) and 10 patients with aldosterone-producing adenomas (APA) under conditions of sodium (150 meq/day) balance. Episodic release of aldosterone and cortisol was assessed by sampling blood at 10-min intervals for 24 h. A waveform-independent deconvolution algorithm was used to calculate endogenous aldosterone and cortisol secretion rates on a sample by sample basis in each subject. There were no differences in the number of aldosterone or cortisol secretory bursts per day or their mean interpulse intervals between normal subjects and patients with primary aldosteronism. A 24-h rhythmicity in serum aldosterone concentrations was maintained in APA patients. Patients with primary aldosteronism had significantly higher (P < 0.01) aldosterone mean secretory rates, mean mass of aldosterone secreted per burst, maximal aldosterone secretion rates attained within each burst, and mean basal (nadir) aldosterone secretion rates. A recently introduced regularity statistic, approximate entropy (ApEn), was used to test for orderliness (small ApEn) vs. randomness (large ApEn) in the aldosterone time series. ApEn was significantly larger for the APA patients (1.433 +/- 0.148) than for normal subjects (0.306 +/- 0.098; P < 0.001), with complete group segmentation yielding 100% sensitivity and specificity. In contrast, a scale-invariant form of this measure, normalized ApEn, showed no significant distinction between tumoral and normal aldosterone release patterns. These ApEn findings taken together are consistent with the deconvolution results from an entirely distinct perspective, reinforcing an amplitude difference, but no frequency difference, between normal subjects and APA patients. Unexpectedly, patients with APA had significantly lower mean cortisol secretory rates, reduced cortisol secretory burst mass, and attenuated maximal cortisol secretory rates than normal subjects (P < 0.01). Plasma cortisol and aldosterone concentrations in patients remained positively correlated over short time lags. In summary, the present findings demonstrate that in normal subjects and patients with APA, both aldosterone and cortisol are secreted in a burst-like mode. The presence of substantial basal aldosterone release and increased irregularity of serial aldosterone concentrations distinguishes APA from normal subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Self-organized segmentation of time series: Separating growth hormone secretion in acromegaly from normal controls

Article

Jul 1996

The pulsatile pattern of growth hormone (GH) secretion was assessed by sampling blood every 10 min over 24 h in healthy subjects (n = 10) under normal food intake and under fasting conditions (n = 6) and in patients with a GH-producing tumor (acromegaly, n = 6), before and after treatment with the somatostatin analog octreotide. Using autocorrelation, we found no consistent separation in the temporal dynamics of GH secretion in healthy controls and acromegalic patients. Time series prediction based on a single neural network has recently been demonstrated to separate the secretory dynamics of parathyroid hormone in healthy controls from osteoporotic patients. To better distinguish the differences in GH dynamics in healthy subjects and patients, we tested time series predictions based on a single neural network and a more refined system of multiple neural networks acting in parallel (adaptive mixtures of local experts). Both approaches significantly separated GH dynamics under the various conditions. By performing a self-organized segmentation of the alternating phases of secretory bursts and quiescence of GH, we significantly improved the performance of the multiple network system over that of the single network. It thus may represent a potential tool for characterizing alterations of the dynamic regulation associated with diseased states.

Females secrete growth hormone with more process irregularity than males in both humans and rats

Article

Feb 1996
Am J Physiol

In humans, serum growth hormone (GH) concentrations are significantly higher in women than in men, but the neuroendocrine mechanisms that underlie such gender differences are not known. We compared normal episodic GH secretion in males and females in three distinct settings: two human studies employing quite different assay techniques (immunoradiometric assay and a high-sensitivity immunofluorimetric method) and a rat study. To quantify the amount of regularity in data, we utilized approximate entropy (ApEn), a scale- and model-independent statistic. In each study, females exhibited significantly greater statistical irregularity in GH concentration series than their male counterparts (P < 10(-3) for each human study, P < 10(-6) for the rat study), implying that mass and mode of GH secretion are regulated differently in males and females. The regularity comparisons indicated complete gender separation (100% specificity and sensitivity) for the rat study and nearly complete separation for the immunofluorimetric assay study. The consistency and statistical significance of these findings suggest that this gender difference may be broadly based within higher animals and that this may be readily evaluated objectively by analysis of ApEn.

The orderliness of the growth hormone (GH) release process and the mean mass of GH secreted per burst are highly conserved in individual men on successive days

Article

Nov 1996

Endocrine glands signal their remote target tissues via physiologically pulsatile release of regulatory molecules. A cardinal assumption of most pathophysiological experiments is that discrete attributes of pulsatile hormone secretion are stable over successive untreated observation intervals; i.e. repeated measurements show serial within-subject reproducibility. To test this hypothesis in the GH axis, we sampled blood every 10 min for 48 h in 14 healthy men (age range, 29-77 yr; body mass index, 21-51 kg/m2). The 2 consecutive 24-h serum profiles were subjected to ultrasensitive GH chemiluminescence assay (sensitivity, 0.002 micrograms/L) with a new dose-dependent variance model to estimate within-assay precision. We then applied deconvolution analysis to estimate the number, mass, amplitude, and duration of underlying GH secretory bursts as well as simultaneously calculate the apparent GH half-life and any concurrent basal hormone secretion. Test-retest consistency was assessed by the Pearson correlation coefficient, and differences were determined by paired nonparametric (Wilcoxon) testing. Comparing successive 24-h profiles, no significant differences existed in any of the foregoing secretion or half-life measures or in a novel estimate of the relative disorderliness of hormone release, namely approximate entropy. Correlation was minimal for secretory burst amplitude and half-duration. In contrast, the calculated mean mass of GH secreted per burst was highly conserved across sessions within subjects, with an r value of 0.932 (P < 10(-6). This correlation equaled or exceeded that of mean and integrated serum GH concentrations on consecutive days (r = 0.920; P = 0.00003). The calculated daily GH production rate was also strongly reproduced (r = 0.784; P = 0.0009). Moreover, the within-subject GH half-life and GH secretory burst frequency estimates were well correlated on successive days (P = 0.034-0.004; r = 0.568-0.711). Approximate entropy values were consistent at r = 0.837 (P = 0.0019). In addition, basal GH secretion rates correlated at r = 0.622 (P = 0.0176). We conclude that homeostatic control mechanisms within the GH-insulin-like growth factor I axis strongly preserve the day to day mean mass of GH secreted per burst and the serial orderliness of the GH release process in individual healthy men across a wide span of ages and body compositions.

Older Males Secrete Luteinizing Hormone and Testosterone More Irregularly, and Jointly More Asynchronously, than Younger Males

Article

Nov 1996

New statistical perspectives on the secretory patterns of both luteinizing hormone (LH) and testosterone (T) may prove useful in further understanding the aging process, and possibly ultimately in improving the diagnosis and treatment of spermatogenetic failure and loss of sexual interest. We examined serum concentration time-series for LH and T in 14 young (21-34 years of age) and 11 aged (62-74 years of age) healthy men. Fur each subject, blood samples were obtained at 2.5-min intervals during a sleep period, with an average sampling duration of 7 hr. For each of LH and T, we used the model-independent statistic approximate entropy (ApEn) to quantify the irregularity of the serum concentration time-series; to quantify, joint LH-T secretory asynchrony, we employed the recently introduced cross-ApEn. Although mean (and SD) LH and T concentrations were indistinguishable in the two age groups (P > 0.25), for LH, aged subjects had greater ApEn values (1.525 ± 0.221) than younger individuals (1.207 ± 0.252), P < 0.003, indicating more irregular secretion in the older cohort. Fur T, aged subjects also had greater ApEn values (1.622 ± 0.120) than younger counterparts (1.384 ± 0.228), P < 0.004. In young, but not older men, ApEn(T) significantly exceeded ApEn (LH), P < 0.02. Aged subjects had greater cross-ApEn values (1.961 ± 0.121) than younger subjects (1.574 ± 0.249), P < 10-4, with nearly 100% sensitivity and specificity, indicating greater LH-T asynchrony in the older group. In conjunction with previous findings of greater irregularity of growth hormone release with increasing age, we propose that increased secretory irregularity with advancing age may be a widespread hormonal phenomenon. Finally, theoretically, we clarify the need for quantifications such as ApEn and cross-ApEn via a study of a 'variable lag' pulsatile process, and empirically note the potential wide applicability of cross-ApEn to quantify asynchrony in interconnected (hormonal) networks.

Greater disorderliness of ACTH and cortisol release accompanies pituitary-dependent Cushing’s Disease

Article

May 1997

We investigated the episodicity of 24-h ACTH and cortisol secretory profiles in 16 patients with Cushing's disease and 25 healthy matched controls, with a recently introduced scale- and modelindependent regularity statistic, approximate entropy (ApEn). The mean (± s.e.m. ) ApEn value for plasma ACTH concentrations in Cushing's disease was 1·3817 ± 0·033, and in controls 0·8394 ± 0·049 ( P < 10 ⁻¹⁰ ); for plasma cortisol concentrations the values were 1·4575 ± 0·052 and 0·8637 ± 0·020 respectively ( P <10 ⁻¹⁰ ), implying greater irregularity of release for both hormones in Cushing's subjects. The calculated sensitivity and specificity of ApEn for ACTH profiles were 94% and 100% respectively. For cortisol the sensitivity and specificity were both 100%. ApEn was not correlated with sex, age, or the total 24-h secretion rate of ACTH and cortisol in patients and controls. The increased ApEn in patients with Cushing's disease points to an increased disorderliness of ACTH and cortisol secretion compared with healthy controls. In conjunction with the available literature, we hypothesize more generally that autonomous endocrine tumors may be typified by reduced regularity, orderliness, or synchrony of the time structure of hormone release. European Journal of Endocrinology 136 394–400

Abdominal adiposity rather than age and sex predicts mass and regularity of GH secretion in healthy adults

Article

Jul 1997
Am J Physiol

We tested the hypothesis that body composition is the major predictor of growth hormone (GH) secretion in nonobese adults. We measured lean and fat tissue distribution (computerized tomography and dual-energy X-ray absorptiometry scan) and physical fitness [maximal oxygen consumption (Vo2max)] in 42 healthy nonobese adults (22 women and 20 men, age range 27-59 yr, mean +/- SE body mass index = 24 +/- 0.5 kg/m2). Deconvolution analysis was used to estimate specific features of 24-h GH secretion and clearance. Approximate entropy was used to quantify the regularity of GH release. Older subjects exhibited decreased estimates of GH secretion compared with younger subjects. Females had higher estimates of GH secretion, a longer GH half-life, and displayed more irregularity in GH release than males. Mean 24-h serum GH concentrations correlated inversely with intra-abdominal fat and waist-to-hip ratio and positively with Vo2max. Multiple linear regression analysis revealed intra-abdominal fat as the dominant determinant of estimates of GH secretion. Vo2max was more important than sex and age in predicting GH secretion. We conclude that abdominal fat is the major determinant of GH secretion in healthy nonobese adults. Although the underlying mechanisms remain elusive, our findings extend the clinical implications of visceral adiposity to include hyposomatotropism.

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

Article

Oct 1997
Am J Physiol

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.

Effects of age on the irregularity of LH and FSH serum concentrations in women and men

Article

Nov 1997
Am J Physiol

We evaluated an apparent distinction between follicle-stimulating hormone (FSH) and luteinizing hormone (LH) dynamics: visually, it appears that the pattern of serum concentrations of FSH is more irregular than that of LH in younger human females. We studied healthy humans, with LH and FSH serum samples obtained every 10 min for 24 h. Three groups were studied: 24 young females [8 early follicular (EFol), 8 late follicular (LFol), and 8 midluteal (MLut)]; 8 postmenopausal females; and 17 males 21-79 yr of age. To quantify serial irregularity, we utilized approximate entropy (ApEn), a scale- and model-independent statistic. For young females, FSH was consistently more irregular than LH per subject: among the younger subjects, ApEn(FSH) - ApEn(LH) = 0.342 +/- 0.270; ApEn(FSH) > ApEn(LH), P < 0.00001; ApEn(FSH) > ApEn(LH) for 23 of 24 subjects. For each cycle stage, pairwise ApEn(FSH) > ApEn(LH): P < 0.005 for both LFol and MLut, P < 0.01 for EFol. Notably, for the postmenopausal women, the irregularity difference vanished:ApEn(FSH) - ApEn(LH) = 0.008 +/- 0.205. Males exhibited qualitatively similar results: ApEn(FSH)- ApEn(LH) was significantly and negatively correlated with age (r = -0.75, P = 0.0006). The capability to quantify (the extent of) differences between FSH and LH release, beyond the general 1:1 correspondence between primary LH and FSH pulses, suggests a means to assess bihormonal changes as a clinical marker of altered reproductive status in a variety of settings, e.g., a perimenopausal milieu. Mechanistically, the erosion of unequal FSH-LH regularity with age is consistent with a loss of synchrony control within the integrated hypothalamo-pituitary-gonadal axis.

Patients with Cushing's disease secrete ACTH and cortisol jointly more asynchronously than healthy subjects

Article

Mar 1998

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.

Differential orderliness of the GH release process in castrate male and female rats

Article

Mar 1998
Am J Physiol

Characteristics of luteinizing hormone secretion in younger versus older premenopausal women

Article

Apr 1998
AM J OBSTET GYNECOL

The objectives of this study were to document specific attributes of pulsatile luteinizing hormone secretion in middle-aged women before discernible alterations in their menstrual cycles and to compare the results to corresponding data obtained in younger women. After documenting normal cycle length, biphasic basal body temperatures, and normal midluteal progesterone in younger and middle-aged women during an initial cycle, daily blood samples and samples withdrawn at 10-minute intervals for 8 hours during the midfollicular phase were obtained during a subsequent cycle. Assessment of luteinizing hormone pulses with the pulse detection algorithm Cluster demonstrated a prolonged interpulse interval and increased pulse width in the older women. Assessment of luteinizing hormone secretory bursts and half-life with the deconvolution analysis procedure demonstrated a prolonged interburst interval and half-life in the older women. Appraisal of approximate entropy revealed greater orderliness of luteinizing hormone release in the older women. Middle-aged women exhibit alterations in hypothalamic-pituitary function that may account in part for age-related changes in reproductive potential.

Not all (possibly) ''random'' sequences are created equal

Article

May 1997

The need to assess the randomness of a single sequence, especially a finite sequence, is ubiquitous, yet is unaddressed by axiomatic probability theory. Here, we assess randomness via approximate entropy (ApEn), a computable measure of sequential irregularity, applicable to single sequences of both (even very short) finite and infinite length. We indicate the novelty and facility of the multidimensional viewpoint taken by ApEn, in contrast to classical measures. Furthermore and notably, for finite length, finite state sequences, one can identify maximally irregular sequences, and then apply ApEn to quantify the extent to which given sequences differ from maximal irregularity, via a set of deficit (def(m)) functions. The utility of these def(m) functions which we show allows one to considerably refine the notions of probabilistic independence and normality, is featured in several studies, including (i) digits of e, pi, radical2, and radical3, both in base 2 and in base 10, and (ii) sequences given by fractional parts of multiples of irrationals. We prove companion analytic results, which also feature in a discussion of the role and validity of the almost sure properties from axiomatic probability theory insofar as they apply to specified sequences and sets of sequences (in the physical world). We conclude by relating the present results and perspective to both previous and subsequent studies.

Increased growth hormone secretory event frequency and plasma insulin-like growth factor-I levels during the preovulatory interval in normal women: assessment by paired within-subject comparisons, ultrasensitive immunofluorometric GH assay, and deconvolution analysis

Jan 1998

P Ovesen
N Vahl
S Fisker
Jd Veldhuis
H Orskov
Js Christiansen

Ovesen P, Vahl N, Fisker S, Veldhuis JD, Orskov H, Christiansen JS et al. Increased growth hormone secretory event frequency and plasma insulin-like growth factor-I levels during the preovulatory interval in normal women: assessment by paired within-subject comparisons, ultrasensitive immunofluorometric GH assay, and deconvolution analysis. Journal of Clinical Endocrinology and Metabolism 1998 (In Press).

Orderliness of hormone release patterns: a complementary measure to conventional pulsatile and circadian analyses

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