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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 6 2863-2869
Copyright © 2002 by The Endocrine Society

Other Original Articles

Increased Orderliness of Growth Hormone (GH) Secretion in GH-Deficient Adults with Low Serum Insulin-Like Growth Factor I

Johan Svensson, Johannes D. Veldhuis, Ali Iranmanesh, Bengt-Åke Bengtsson and Gudmundur Johannsson

Research Centre for Endocrinology and Metabolism (J.S., B.-Å.B., G.J.), Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden; General Clinical Research Center, Department of Medicine, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 22908; and Salem Veterans Affairs Medical Center (A.I.), Salem, Virginia 24153

Address all correspondence and requests for reprints to: Johan Svensson, M.D., Research Centre for Endocrinology and Metabolism, Gröna Stråket 8, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail: . johan.svensson{at}medic.gu.se

Abstract

Available studies suggest that a proportion of GH-deficient (GHD) adults maintain serum IGF-I concentrations within the age- and sex-matched normal range. The basis for this distinction is not known. In this study 24-h GH profiles (sampling every 30 min) were appraised in five GHD adults with low serum IGF-I concentrations (<2 SD of the age- and sex-matched normal range), five GHD adults with normal serum IGF-I levels (within ±2 SD), and five healthy subjects. Serial GH concentrations, measured using a chemiluminescence assay, were analyzed by deconvolution and approximate entropy (ApEn; regularity) analyses.

The apparent half-duration of GH secretory bursts was longer in both GHD groups than in the healthy controls, as determined by deconvolution analysis (P < 0.05 each). The GH burst frequency was higher, the interburst interval was shorter, and the GH burst amplitude was lower in GHD adults with normal serum IGF-I than in healthy controls (P < 0.05, P < 0.05, and P < 0.01, respectively). The percentage of total daily GH secretion that was pulsatile was also reduced in the GHD adults with normal serum IGF-I compared with the other two groups (P < 0.05 and P < 0.05, respectively). In contrast, ApEn ratios were lower in the GHD adults with low serum IGF-I than in the GHD adults with normal IGF-I and controls (P < 0.01 and P < 0.05, respectively). Serum IGF-I concentrations correlated positively with ApEn ratios in the total study population (n = 15) and in the GHD adults (n = 10).

In conclusion, 24-h patterns of GH release differed in GHD adults with low vs. normal serum IGF-I concentrations. GHD adults with low IGF-I levels maintain low ApEn ratios (denoting greater relative orderliness of GH secretion), whereas GHD patients with normal IGF-I values generate a high frequency, low amplitude GH output. The foregoing contrasts point to distinct neuroendocrine features of the GH-deficient state of adults, which can be related to concurrent IGF-I production.

IN RATS, THE secretory pattern of GH is gender specific and regulates the sexual dimorphism of liver enzymes and other tissue responses (1, 2). Premenopausal women have relatively elevated and more irregular patterns of daily GH secretion and higher serum total IGF-I concentrations than men of comparable age (3, 4, 5, 6, 7). Pubertal studies in humans further suggest that reduced orderliness of GH release, estimated using approximate entropy (ApEn) analysis, is associated with greater endogenous IGF-I generation (8, 9).

Several studies show that most GH-deficient (GHD) adults have detectable GH concentrations, as measured by highly sensitive GH assays (10, 11). Pulsatile GH secretion persists at low GH concentrations in patients treated for hypothalamic-pituitary disease with surgery and irradiation (12). Serum IGF-I concentrations are generally low in children (13) and in young adults with GHD (14). In study groups including both young and elderly GHD adults, however, up to 50% of patients have serum IGF-I concentrations within ±2 SD of the age- and sex-matched normal range (15, 16, 17). Little is known about the relationship between the GH secretory pattern and serum IGF-I concentrations in GHD adults.

In this study the aim was to determine whether the secretory pattern of GH release differed in GHD adults with low vs. normal serum IGF-I concentrations. The GHD patients were therefore divided into a GHD group with low (IGF-I SD score below -2 SD) and normal (IGF-I SD score within ±2 SD) serum IGF-I concentrations. This division may be of clinical relevance, because in GHD adults with low baseline serum IGF-I concentrations, one of the major aims is to normalize serum IGF-I concentrations (18). In GHD adults with normal serum IGF-I concentrations, dose titration is mainly based on normalizing body composition and quality of life (18). Twenty-four-hour plasma GH profiles (sampling every 30 min) were monitored in GHD adults with low serum IGF-I concentrations, in GHD adults with normal serum IGF-I, and in healthy subjects. Plasma GH concentrations were analyzed using a highly sensitive chemiluminescence assay, and GH secretory patterns were determined using deconvolution and ApEn analysis (below).

Subjects and Methods

Patients

Five adult GHD patients with low serum IGF-I concentrations (below -2 SD of the age- and sex-matched normal range) and five adult GHD patients with normal serum IGF-I concentrations (within ±2 SD) were asked to participate in this study. In addition, five healthy subjects were recruited. The diagnosis of GHD in all patients was based on a maximum peak GH response of less than 3 µg/liter during an insulin tolerance test (blood glucose, <=2.2 mmol/liter) performed in adulthood life. The pituitary deficiency was mainly caused by pituitary tumors or their treatment (Table 1Go). No patient had previous acromegaly. All patients with childhood-onset GHD had received GH treatment during childhood, which had been discontinued at least 2 yr before entering this study.


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  		Table 1. Causes of pituitary deficiency and the type of pituitary deficiency in the 10 GH-deficient adults

 
All patients with ACTH deficiency received a standard glucocorticoid replacement with cortisone acetate (12.5 mg at 0700 h and 12.5 mg at 1500 h), thyroid hormones, gonadal steroids, and desmopressin when required. The doses of levothyroxine (time of treatment, 0700 h) were 0.15, 0.15, 0.1, 0.1, and 0.05 mg, respectively, in the TSH-deficient GHD patients with normal serum IGF-I concentrations and 0.15, 0.1, and 0.1 mg, respectively, in the TSH-deficient GHD patients with low serum IGF-I concentrations. All hypogonadal men received standard T replacement with 250 mg T, im, every fourth week. In the GHD group with normal serum IGF-I concentrations, one female patient received oral estrogen treatment (2 mg E2 daily), whereas one gonadotropin-deficient female patient did not receive estrogen substitution. In the low IGF-I group, one female patient received transdermal estrogen treatment (50 µg/24 h), whereas the other female patient was receiving oral contraceptives (75 µg levonorgestrel daily and 40 µg ethinyl E2 daily).

In the GHD group with normal serum IGF-I concentrations, one patient received oral cholestyramine for a high serum total cholesterol concentration and a diuretic (2.5 mg bendroflumethiazide daily) for hypertension. In the GHD group with low serum IGF-I concentrations, one patient received a low dose of clomipramide (10 mg daily) to treat anxiety. The controls did not take any medication.

Study protocol

This was a prospective study. The GH secretory status was assessed by 24-h GH measurements (beginning at 1000 h) from repeated 30-min blood sampling using a withdrawal pump. Plasma GH concentrations and GH secretory patterns were analyzed (blinded) by deconvolution analysis and analysis of ApEn.

The patients and the controls were allowed to maintain their ordinary consumption of caffeine and/or tobacco during the profiles. Ingestion of alcohol was not allowed the day before the profiles or during the profiles. The patients were allowed to move freely within the ward. Standardized meals were given at 0800, 1200, 1600, and 1900 h. The patients were instructed to go to bed at the same time as they used to do at home.

Ethical considerations

The study was approved by the ethical committee of the University of Goteborg, and informed consent was obtained from each subject before the start of the study.

Body mass index (BMI) and waist to hip ratio

Body weight was measured in the morning to the nearest 0.1 kg using a 6800 Digital Indicator (Detecto Scale, Webb City, MO) after the subjects had voided. Body height was measured barefoot and to the nearest 0.5 cm. BMI was calculated using the formula: BMI = body weight (kilograms)/height2 (meters).

Waist circumference was measured with a soft tape midway between the lowest rib margin and the iliac crest in the standing position. Hip circumference was measured over the widest part of the gluteal region, and the waist to hip ratio was calculated.

Deconvolution analysis

Two-compartment deconvolution analysis was applied as described previously (19). Fixed GH half-lives were used (fast component, 3.5 min; slow component, 20.9 min; fractional amplitude of slow component, 0.63) as previously determined directly in GHRH-stimulated and then somatostatin-suppressed adults (20). The daily pulsatile GH secretion is the product of secretory burst frequency and the (mean) mass of GH released per pulse. Basal secretion represents the time-invariant interpulse component of the GH release profile (21). Analysis was carried out requiring 95% joint statistical confidence intervals for all GH secretory burst amplitudes (6, 22). The analyst was blinded to the time series assignments.

ApEn

ApEn quantifies the serial orderliness of pattern regularity of the (hormone) release process over 24 h (8). ApEn parameters of m = 1 (series length) and r = 20% (threshold) of the intraseries SD were used, as described previously (23). ApEn was normalized by calculating the ratio of observed to 1000 randomly shuffled versions of each GH time series. Thus, ApEn ratios approaching 1.0 denote the mean expected random behavior. A higher absolute ApEn ratio (at equal series lengths and parameter values as used here) denotes greater disorderliness (randomness) of moment to moment hormone release as observed previously for GH in acromegaly (24) and in women compared with men (23).

Biochemical assays

Plasma GH concentrations were measured using an ultrasensitive chemiluminescence assay with a lower limit of detectability of 0.002 µg/liter (at 2 SD above the assay blank) and 0.005 µg/liter (at 3 SD above the assay blank), as previously described (22). The median intra- and interassay CVs were less than 7.5%. All plasma samples from an individual were assayed together.

Blood samples for the determination of serum IGF-I concentration were drawn in the morning after an overnight fast. The serum IGF-I concentration was determined by a hydrochloric acid-ethanol extraction RIA using recombinant human IGF-I for labeling (Nichols Institute Diagnostics, San Juan Capistrano, CA). Inter- and intraassay coefficients of variation were 5.4% and 6.9%, respectively, at a mean serum IGF-I concentration of 126 µg/liter. Individual serum IGF-I values were compared with age- and sex-adjusted values obtained from a reference population of 197 men and 195 women (5). The individual IGF-I SD scores could then be calculated (17).

Serum insulin was determined by RIA (Phadebas, Pharmacia Biotech, Uppsala, Sweden).

Statistics

Descriptive statistical results are presented as the median and range. Between-group differences were calculated using the Kruskal Wallis ANOVA test by ranks. Post hoc analyses were performed using the Mann-Whitney U test. Correlations were determined using the Spearman rank order correlation test. A two-tailed P <= 0.05 was considered significant.

Results

Clinical characteristics and serum IGF-I concentrations (Table 2Go)

There was a tendency for age to be lower in the GHD group with low IGF-I. All groups were comparable with regard to sex and BMI. The duration of hypopituitarism, defined as the time from the discovery of the first anterior pituitary hormone deficiency to the time of the study, was similar in the two GHD groups. Serum IGF-I concentrations and IGF-I SD scores were lower in the GHD group with low serum IGF-I concentrations than in the two other study groups.


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  		Table 2. Characteristics in the study population of 5 healthy subjects and 10 GHD adults

 
The waist to hip ratio and serum insulin concentration were similar in the two GHD groups (Table 2Go). The waist to hip ratio and serum insulin concentration were not determined in the controls.

Deconvolution analysis (Table 3Go)

Basal GH secretion rates (micrograms per liter/minute) were statistically similar in the three groups, although there was a tendency for basal GH secretion to be higher in the GHD group with normal IGF-I concentrations than in the other two groups. Apparent GH secretory burst half-duration was longer in the both GHD groups than in the healthy controls (P < 0.05 and P < 0.05, respectively). The GH burst frequency was higher, the interburst interval was shorter, and the GH burst amplitude was lower in the GHD adults with normal serum IGF-I levels than in healthy controls (P < 0.05, P < 0.05, and P < 0.01, respectively). The mean GH concentration, integrated area, total production rate, and pulsatile production rate were similar among the three groups. The percent pulsatile GH secretion was lower in the GHD adults with normal serum IGF-I than in the other two groups (P < 0.05 and P < 0.05, respectively).


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  		Table 3. Deconvolution analysis of 24-h plasma GH concentration profiles in 5 healthy subjects and 10 GHD adults

 
ApEn ratios

ApEn ratios were lower in the GHD adults with low serum IGF-I than in the GHD adults with normal IGF-I or the controls (P < 0.01 and P < 0.05, respectively; Fig. 1AGo), denoting relatively more regular patterns of GH release.



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  		Figure 1. A, ApEn ratios obtained from 24-h plasma GH concentration profiles in 5 healthy controls and 10 GHD adults. Values are presented as the median and range. B, Positive correlation in the 10 GHD adults between serum IGF-I concentration and ApEn ratio. An ApEn ratio approaching 1.0 denotes approximately random GH profiles (indistinguishable from 1000 randomly shuffled versions of the same data series; see Subjects and Methods).

 
Correlations

In the GHD adults (n = 10), serum IGF-I concentrations correlated positively with ApEn ratios (r = 0.81; P < 0.01; Fig. 1BGo) and negatively with percent pulsatile GH secretion (r = -0.69; P < 0.05; Fig. 2AGo). Serum IGF-I concentrations did not correlate with basal GH secretion rate (Fig. 2BGo), GH burst frequency (Fig. 2CGo), GH burst amplitude (Fig. 2DGo), or any other secretory variable.



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  		Figure 2. The inverse correlation between serum IGF-I concentration and percent pulsatile GH secretion (r = -0.69; P < 0.05) is shown in A. B–D, Scatter plots between serum IGF-I concentration and basal GH secretion rate (B), GH burst frequency (C), and GH burst amplitude (D).

 
In the total study population (n = 15), serum IGF-I concentrations correlated positively with ApEn ratios (r = 0.54; P < 0.05). The serum IGF-I concentration was not correlated with any other secretory variable.

In the GHD adults as well as in the total study population, age was not correlated with the serum IGF-I concentration (r = 0.12 and r = 0.14, respectively), the ApEn score (r = 0.26 and r = 0.18, respectively), or GH secretory variables.

Discussion

This study distinguishes patterns of daily GH release in GHD adults with low serum and normal serum IGF-I concentrations. As estimated by deconvolution analysis, the percentage of total daily GH secretion that was pulsatile was lower in GHD adults with normal serum IGF-I concentrations than in GHD adults with low serum IGF-I levels and healthy controls. This abnormality was associated with low amplitude and high frequency GH pulses in the GHD adults with normal serum IGF-I levels. ApEn analysis further demonstrated lower ApEn ratios (higher orderliness of GH secretion) in the GHD adults with low IGF-I than in the other two groups. The latter finding was extended by showing that the serum IGF-I concentration was positively related to ApEn estimates (below).

In this study blood sampling was performed every 30 min over 24 h. Previous validation of the deconvolution analysis showed valid daily GH secretion rate estimates based on 30-min sampling, although the sensitivity for absolute peak number was lower than that using 10- to 20-min sampling schedules (25). Thus, the present data for absolute pulse number and width will be important to confirm using more intensive sampling paradigms. Even so, only patients with GHD and normal IGF-I concentrations exhibited significantly higher frequency and lower amplitude GH pulses (below). Analysis of normalized ApEn is less dependent on the sampling frequency, in as much as every 60-min sampling protocol yielded strong contrasts between acromegaly and normal GH secretory patterns (8, 9).

Age tended to be lower in the patients with low serum IGF-I than in the other groups. In normal aging, pulsatile GH secretion is decreased, and the ApEn score is increased (22). Although no correlation was found between age and GH secretory patterns, one cannot fully exclude some impact of the tendency toward a lower age in the low IGF-I group on the higher percent pulsatile secretion of GH and the lower ApEn score observed in this group compared with the normal IGF-I group. On the other hand, the present findings are consistent with the hypothesis that younger GHD patients have lower serum IGF-I concentrations (13, 14), whereas a larger proportion of elderly GHD adults have normal serum IGF-I concentrations (15, 16, 17). Furthermore, in the present study the sample size was small. No difference was observed between the normal subjects and the two GHD groups in mean GH concentration, integrated area, total production rate, or pulsatile production rate. This could be due to the relatively small number of subjects included in this study.

GHD patients with normal IGF-I concentrations exhibited the greatest detectable GH pulse frequency along with the lowest amplitude events. This anomalous secretory pattern explains the lower percentage of total daily GH secretion that was pulsatile in this cohort. Although low amplitude, pulsatile GH secretion persists in GHD adults (present data and Ref. 12), GH secretion is more nearly continuous in GHD adults with normal than low serum IGF-I concentrations. There are several indications that a more continuous (feminized) pattern of GH delivery to the liver may be more effective in stimulating IGF-I generation than a pulsatile mode. Premenopausal women have elevated interpulse GH concentrations (3, 4, 6, 7), higher ApEn scores (23), and higher serum IGF-I concentrations (5) than men of a similar age. In acromegaly, increased serum IGF-I concentrations are closely related to the nonpulsatile component of GH secretion (26, 27, 28). Indeed, the present study documents a negative correlation in GHD adults between the serum IGF-I concentration and the percentage of daily GH secretion that was pulsatile.

In the GHD adults with low serum IGF-I concentrations, the mean ApEn score was lower, which quantitates relatively greater orderliness of GH secretion than in the other two study groups. Higher serum IGF-I concentrations were strongly related to higher GH ApEn ratios (heightened irregularity) in the total study population as well as in the GHD adults. In line with this new observation, more disorderly GH secretion patterns (increased ApEn) were observed in puberty and acromegaly (8, 9) as well as under exogenous GHRH and/or GH-releasing peptide-2 drive (9, 29, 30, 31, 32). Thus, the irregularity of GH secretion is increased in pathophysiological, physiological, and experimental conditions marked by stronger feedforward drive of GH secretion (33). In this regard, administration of estrogen and T also elevates GH ApEn, consistent with the idea of greater endogenous secretagogue actions during sex steroid repletion (34, 35). Conversely, continuous iv infusions of recombinant human IGF-I or somatostatin repress GH ApEn values (33, 36), consistent with the expected effectual antagonism of endogenous feedforward signaling by negative feedback. The fact that lower serum IGF-I concentrations were accompanied by suppression of ApEn in the corresponding GHD cohort strongly suggests that such lower ApEn values reflect greater impairment of endogenous GH secretagogue feedforward in these patients rather than accentuated IGF-I negative feedback.

Pulsatile GH secretion is regulated by the synchrony between GHRH release and somatostatin withdrawal (37). Accordingly, one could speculate that GHD adults with normal IGF-I concentrations maintain less relative hypothalamic somatostatin restraint of GH release (and/or greater GHRH/GH-releasing peptide output; see above). The degree and character of the hypothalamic neuroendocrine dysfunction may decide whether a normal or a low serum IGF-I concentration is maintained.

In conclusion, despite comparable mean serum GH concentrations, the patterns of GH release differ between GHD adults with low and normal serum IGF-I concentrations. GHD adults with low IGF-I levels exhibit decreased GH ApEn ratios, signifying greater relative orderliness of GH secretion patterns. GHD adults with normal IGF-I concentrations maintain a more continuous low amplitude, high frequency pattern of GH secretion than the GHD adults with low IGF-I values. The present data thus indicate that the nature of the neuroendocrine abnormality associated with the GH deficiency state in the adult predicts the degree of suppression of the serum IGF-I concentration. Further studies will be required to elucidate the precise neuroadaptive mechanisms mediating this distinction and assess its applicability to children with GHD.

Acknowledgments

We are indebted to Lena Wirén, Anne Rosén, Ingrid Hansson, and Sigrid Lindstrand (Research Center for Endocrinology and Metabolism, Sahlgrenska University Hospital) and Olof Ehn (Department of Endocrinology, Sahlgrenska University Hospital) for their skillful technical support.

Footnotes

This work was supported by grants from the Swedish Medical Research Council (no. 11621) and the NIH (AG-O1499 and RR-MO10647 to the General Clinical Research Center of the University of Virginia).

Abbreviations: ApEn, Approximate entropy; BMI, body mass index; GHD, GH deficient.

Received September 6, 2001.

Accepted March 6, 2002.

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C. Franco, J. D Veldhuis, A. Iranmanesh, J. Brandberg, L. Lonn, B. Andersson, B.-A. Bengtsson, J. Svensson, and G. Johannsson
Thigh intermuscular fat is inversely associated with spontaneous GH release in post-menopausal women with abdominal obesity.
Eur. J. Endocrinol., August 1, 2006; 155(2): 261 - 268.
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J. Svensson, G. Johannsson, A. Iranmanesh, K. Albertsson-Wikland, J. D Veldhuis, and B.-A. Bengtsson
GH secretory pattern in young adults who discontinued GH treatment for GH deficiency and decreased longitudinal growth in childhood.
Eur. J. Endocrinol., July 1, 2006; 155(1): 91 - 99.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
A. Mukherjee, J. P. Monson, P. J. Jonsson, P. J. Trainer, and S. M. Shalet
Seeking the Optimal Target Range for Insulin-Like Growth Factor I during the Treatment of Adult Growth Hormone Disorders
J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5865 - 5870.
[Abstract] [Full Text] [PDF]

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