Search Results

You are looking at 1 - 10 of 22 items for

  • Author: Johannes D Veldhuis x
Clear All Modify Search
Restricted access

Johannes D Veldhuis

Major gender differences exist in the prevalence and severity of various disease states, rates of organ-specific aging and drug and hormone metabolism. Increased understanding of the mechanistic bases for these important sex differences is likely to stimulate new prognostic, therapeutic and diagnostic insights over many succeeding decades. I will outline clinical data that bear on regulatory mechanisms that give rise to sex-based differences in the neuroendocrine activity of the human somatotropic (GH) axis. Such studies have important implications in both pubertal and gonadoprival states, such as aging and the menopause, when the sex-steroid milieu changes dramatically.

Like other neuroendocrine axes, regulation of the hypothalamo-pituitary GH axis in humans and in experimental animals is subject to prominent sex effects (reviewed in Refs. 1–7). For example, most recently we have found, first, that whereas there are profound dependencies of mean (24-h) serum GH concentrations in men on age, body composition (e.g. percentage

Free access

Ali Iranmanesh and Johannes D Veldhuis

Background

ACTH secretion is under hypothalamic stimulatory (feedforward) and adrenal inhibitory (feedback) control.

Hypothesis

Assessment of overnight ACTH secretion during a hypocortisolemic clamp will permit the estimation of changing feedforward and feedback.

Subjects

Seven healthy men.

Interventions

An oral dose of placebo (PLAC), metyrapone (METY, 3 g), or ketoconazole (KTCZ, 1.2 g) was given at midnight (MN) to block glucocorticoid synthesis. Plasma ACTH was sampled every 10 min (MN to 0800 h).

Analysis

Variable-waveform deconvolution analysis of ACTH secretion and approximate entropy (ApEn) analysis of pattern regularity.

Results

Compared with PLAC, administration of METY and KTCZ reduced morning cortisol concentrations by ≥77 and 54% respectively (P<0.001). Hypocortisolemia elevated pulsatile ACTH secretion by 8.2- (METY) and 5.3-fold (KTCZ; both P<0.001). Basal ACTH secretion rose by 3.4-fold under METY-induced cortisol depletion (P=0.020). ACTH secretory-burst shape and half-life were stable. ApEn of ACTH release declined overnight (P=0.021) and with the drug (P=0.001), denoting enhanced feedforward coordination.

Conclusion

The combined data predict overnight amplification and coordination of hypothalamic feedforward drive onto ACTH release. Therefore, disruption of either mechanism might contribute to clinical pathophysiology, such as late-day elevations of cortisol output in fasting, alcoholism, depression, or aging.

Restricted access

Ali Iranmanesh, German Lizarralde and Johannes D Veldhuis

In the present study, we investigated the coordinate kinetic response of the corticotropic axis to the acute metabolic stress of hypoglycemia by applying deconvolution analysis to adrenocorticotropin (ACTH), β-endorphin and cortisol concentration-time series generated in seven normal men after intravenous administration of insulin. Hypoglycemic stress resulted in a 22-fold increase in the mean plasma concentration of ACTH to a maximum of 77±15 pmol/l, in conjunction with a 7.5-fold increase in the mean plasma β-endorphin concentration, the maximal value of which was 96±11 pmol/l. Plasma cortisol concentrations increased by 2.6-fold with a mean value of 734±14 nmol/l. Maximal plasma ACTH and β-endorphin concentrations were preceded by discrete secretory bursts with peak amplitudes of 10.5±2.7 and 10.6±2.0 pmol·I−1·min−1 (20-fold and ninefold increases compared to control), respectively. The mass of ACTH released was 114±20 pmol/l (3.4-fold increase), which corresponds to a total amount of 1.25 μg (50% of daily production and 0.5% of reported pituitary stores), assuming a distribution volume of 40 ml/kg. A total amount of 4.4±0.7 mg of cortisol was released after insulin-induced hypoglycemia, based on a mean cortisol secretory mass of 1088±137 nmol/l and a presumed 11.3-1 volume of distribution. Deconvolution-based estimates of the endogenous half-lives of ACTH, β-endorphin and cortisol were 17±0.6, 22±1.7 and 65±5.3 min, respectively. In summary, deconvolution analysis revealed a rapid coordinate activation of ACTH, β-endorphin and cortisol secretion after hypoglycemic stress, which correlated closely but temporally preceded increases in the respective plasma concentrations. Our inference that only a small fraction of pituitary ACTH content is released during hypoglycemic stress emphasizes the large reserve capability of the pituitary corticotropes. The percentage response of adrenal gland to the metabolic stress of hypoglycemia was of lesser magnitude, possibly owing to the rate-limiting properties of cortisol biosynthesis. We conclude that kinetic responses of the hypothalamic—pituitary—adrenal axis to hypoglycemic stress exhibit exquisite temporal synchrony and manifest a marked reserve capacity.

Free access

Johannes D Veldhuis and Daniel M Keenan

Background

GH pulses are putatively initiated by hypothalamic GH-releasing hormone (GHRH), amplified by GH-releasing peptide (GHRP), and inhibited by somatostatin (SS).

Objective

To ascertain how secretagogues control the waveform (time evolution of release rates) as well as the mass of secretory bursts.

Design

We quantified the shape of GH secretory bursts evoked by continuous combined i.v. infusion of maximally effective doses of GHRH and GHRP-2, and by bolus injection of each peptide after delivering l-arginine to restrain hypothalamic SS release in 12 healthy young men.

Methods

A mathematically verified and experimentally validated variable-waveform deconvolution model was applied to intensively sampled GH time series.

Results

The secretory-burst mode (time from burst onset to maximal secretion) was 19±0.69 min during saline infusion, and fell to a) 10.4±3.0 min during constant dual stimulation with GHRH/GHRP-2 (P<0.01), b) 14.6±1.8 min after l-arginine/GHRH (P<0.025), and c) 15.0±1.0 min after l-arginine/GHRH (P<0.01). Secretagogues augmented the mass of GH secreted in pulses by 44-, 42-, and 16-fold respectively, over saline (2.2±0.81 μg/l per h; P<0.001 for each). Pulse number and variability were unaffected. Applying the same methodology to ten other young men with acute leuprolide-induced hypogonadism yielded comparable waveform and mass estimates.

Conclusion

The present analyses in men demonstrate that peptidyl secretagogues modulate not only the magnitude but also the time course of the GH-release process in vivo independently of the short-term sex-steroid milieu.

Restricted access

Vincenzo Guardabasso, Alessandro D. Genazzani, Johannes D. Veldhuis and David Rodbard

Abstract.

A new objective method is presented for investigating the presence of a temporal relationship between episodic release of two hormones. The two time series of hormone concentrations are first analysed by an objective method for peak detection. Both data series are then transformed into "quantized" or discretized series by recording the occurrence of a hormone pulse as an "event", characterized by the onset, the maximum, or another unique feature. The two quantized series are then matched, and the number of concordant events and discordant events are counted. Each point in series A is compared with a "time-window" of a selected number of points in series B, to accommodate small degree of mismatch between events in the two series. An index of concordance is computed, compensating for any spurious random coincidence: the "Specific Concordance", to evaluate the frequency of concordant events in excess of those expected on the basis of chance alone. This calculation is systematically repeated, interposing a range of time-lags between the two series. A graph of Specific Concordance versus time-lag indicates the time-lag corresponding to a maximal concordance. Simulations of random series of events are performed, and their degree of concordance is evaluated in a similar fashion, thus generating frequency distributions of Specific Concordance values under the null hypothesis of no temporal relationship. This permits the selection of criteria for statistical significance at any desired p-level, for one or many lag times, and for one or multiple subjects. Various degrees of concordance can also be simulated to evaluate the performance (sensitivity, statistical power) of this approach. These methods have been implemented as a collection of short microcomputer programmes, and applied to the study of the temporal relationship between β-endorphin and cortisol in normal subjects sampled every 10 min for 24 h. This analysis demonstrated concordance between events in the two series, with synchronous occurrence of β-endorphin and cortisol release events significantly more frequently than expected on the basis of random association (p<0.01).

Free access

Ferdinand Roelfsema, Hanno Pijl, Daniel M Keenan and Johannes D Veldhuis

Background

The ACTH–cortisol axis in women is activated and associated with decreased ACTH potency, estimated by relating ACTH and cortisol pulse masses. Recently, a new accurate method for constructing the endogenous dose–response relationship was introduced, which is based on the relation between ACTH concentrations and associated cortisol secretion rates within cortisol bursts.

Hypothesis

The endogenous dose–response relation between ACTH and cortisol in obesity is changed, leading to diminished responsiveness.

Subjects

Twenty-five obese premenopausal women and 16 normal weight premenopausal women were studied by 10-min blood sampling for 24 h.

Outcomes

ACTH and cortisol secretion rates, analytical dose–response estimates of endogenous ACTH efficacy (maximal cortisol secretion), dynamic ACTH potency, and adrenal sensitivity (slope term) from 24-h ACTH–cortisol profiles were quantified.

Results

The initial potency (negative logarithm) was −7.83±0.75 (mean±s.e.m.) in obese women and −10.14±1.08 in lean women (P=0.10), and the corresponding values for the recovery phase were −26.62±2.21 and −36.67±1.66 (P=0.004). The sensitivity (curve slope) amounted to 0.468±0.05 in obese women and 0.784±0.09 in normal weight women (P=0.004). The efficacy (maximal value) was 17.6±4.9 nmol/l per min in obese women and 26.3±3.8 nmol/l per min in normal weight women (P=0.009). Basal secretion rate, inflection point, and EC50 values were not different. Bromocriptine or acipimox did not change the dose–response curve.

Conclusion

The ACTH–cortisol relation in obesity in women is characterized by decreased sensitivity and efficacy, thus explaining non-elevated serum cortisol concentrations despite increased plasma ACTH levels.

Restricted access

Johannes D Veldhuis, Ali Iranmanesh, Michael J Wilkowski and Eugeniusz Samojlik

Veldhuis JD, Iranmanesh A, Wilkowski MJ, Samojlik E. Neuroendocrine alterations in the somatotropic and lactotropic axes in uremic men. Eur J Endocrinol 1994;131:489–98. ISSN 0804–4643

To investigate the pathophysiology of altered growth hormone (GH) and prolactin secretion in endstage renal disease, we sampled blood at 10-min intervals for 24 h and applied deconvolution analysis to calculate hormone half-lives and pulsatile secretion rates. Two-site immunoradiometric assays were employed to quantitate presumptively intact GH and prolactin in nine middle-aged men with chronic renal failure and 14 gender-, age-, body weight- and community-matched controls. We observed that the half-lives of endogenous GH and prolactin were prolonged significantly in uremia: for GH, control 17 ±1.4 versus uremia 21 ±1.3 min (p < 0.05); for prolactin, control 66 ±9.3 versus uremia 112 ± 10 min (p < 0.01). Daily GH secretion rates exceeded sex-, age- and weight-predicted values in eight of nine uremic individuals, while values for prolactin were variable but on average twofold higher in uremia. In both the somatotropic and lactotropic axes, the frequency of secretory bursts was increased significantly (for GH, control 11 ± 1.1 versus uremia 15 ± 0.84 secretory events/24 h; for prolactin, control 20 ± 0.90 versus uremia 27 ± 1.3 pulses/24 h. p < 0.05). Although there were no significant alterations in the mean amplitude, duration or mass of GH secretory bursts, prolactin secretory burst amplitudes were elevated threefold in uremia (p < 0.01). These distinctive mechanisms brought about higher 24-h mean serum concentrations of GH (0.70 ±0.17 control versus 1.22 ± 0.32 μg/l uremia) and prolactin (7.3 ± 2.4 control versus 26 ± 6.1 μg/l uremia, p < 0.05). Lastly, serum concentrations of estradiol were increased but those of unconjugated estriol decreased in uremia. We conclude that hypersomatotropinemia and hyperprolactinemia in uremic men result from prolonged hormone half-lives combined with increased frequencies of secretory events driven by unknown stimuli within the respective axes, and/or by defects in their negative-feedback regulation. We postulate that the latter may arise from partial tissue resistance to hormone action in hemodialyzed men.

JD Veldhuis, Division of Endocrinology, Department of Internal Medicine, National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA

Restricted access

Johannes D Veldhuis, Michael L Johnson, Eugene Seneta and Ali Iranmanesh

We have applied explicit probability equations to assess possible non-random associations among four distinct hormone series consisting of episodic luteinizing hormone, follicle stimulating hormone, β-endorphin, and/or cortisol pulses observed under physiological conditions in normal men. Closed-form likelihood functions permitted us to demonstrate significantly coordinated patterns of multiple hormone release. A specific quadruple co-pulsatility pattern was observed, in which the two gonadotropic hormones (luteinizing hormone and follicle stimulating hormone) were co-secreted and coupled by a 10-20 min lag to the later release of β-endorphin. In turn, β-endorphin release episodes were followed within 0–30 min by cortisol bursts. Conditional probability analysis allowed us to reject with high statistical confidence the null hypothesis that this unique temporally specified pattern of quadruple hormone release was due to purely random associations among the four pulsatile series. We conclude that discrete hormone release episodes associated with four hormones within the gonadotropic and corticotropic axes in man exhibit significantly lagged non-random temporal coupling in vivo.

Free access

Ali Iranmanesh, Cyril Y Bowers and Johannes D Veldhuis

Design

While androgens and estrogens control glucocorticoid secretion in animal models, how the sex-steroid milieu determines cortisol secretion in humans is less clear. To address this issue, cortisol was measured in archival sera obtained at 10-min intervals for 5 h in 42 healthy men administered double placebo, placebo and testosterone, testosterone and dutasteride (to block 5α-reductases type I and type II), or testosterone and anastrozole (to block aromatase) in a double-blind, placebo-controlled, prospectively randomized design.

Methods

Subjects received i.v. injection of saline, GHRH, GH-releasing peptide-2 (GHRP-2), somatostatin (SS), and GHRP-2/GHRH/l-arginine (triple stimulus) each on separate mornings fasting. Outcomes comprised cortisol concentrations, pulsatile cortisol secretion, and relationships with age or abdominal visceral fat (AVF).

Results

By ANCOVA, baseline (saline-infused) cortisol concentrations (nmol/l) did not differ among the sex-steroid milieus (overall mean 364±14). In contrast, stimulated peak cortisol concentrations were strongly determined by secretagogue type (P<0.001) as follows: triple stimulus (868±27)>GHRP-2 (616±42)>saline=SS=GHRH (grand mean 420±21). After GHRP-2 injection, pulsatile cortisol secretion increased with age (R 2=0.16, P=0.012). After the triple stimulus, pulsatile cortisol secretion correlated i) inversely with serum 5α-dihydrotestosterone (DHT) concentrations (R 2=0.53, P=0.026) and ii) directly with computerized tomography-estimated AVF (R 2=0.11, P=0.038).

Conclusion

Age, DHT concentrations, AVF, and secretagogue type influence pulsatile cortisol secretion at least in men. Further studies should be performed to assess ACTH secretion and native ghrelin action in defined sex-steroid milieus.