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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0336
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4177-4183
Copyright © 2005 by The Endocrine Society

Joint Mechanisms of Impaired Growth-Hormone Pulse Renewal in Aging Men

Johannes D. Veldhuis, Ali Iranmanesh and Cyril Y. Bowers

Endocrine Research Unit Department of Internal Medicine (J.D.V.), Mayo School of Graduate Medical Education, Mayo Clinic, Rochester, Minnesota 55905; Endocrine Service (A.I.), Research and Development, Salem Veterans Affairs Medical Center, Salem, Virginia 24153; and Division of Endocrinology and Metabolism (C.Y.B.), Department of Internal Medicine, Tulane University Medical Center, New Orleans, Louisiana 70112-2699

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Endocrine Research Unit, Department of Internal Medicine, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Aging reduces the size (mass) of GH secretory bursts and thereby reduces total GH secretion. Experimental data indicate that high-amplitude GH pulses are evoked by reversible cycles of GH-induced negative feedback. Whether aging impairs autofeedback is unknown.

Objective: The objective of this study is to assess whether age attenuates and IGF-I potentiates negative feedback by a near-physiological pulse of GH.

Design/Setting/Subjects: In a university setting, 17 healthy men ages 19–71 yr each underwent four randomly ordered infusion studies on separate mornings fasting.

Intervention: Intravenous injection of a pulse of: 1) saline or 2) recombinant human (rh) GH to impose controlled negative feedback, followed in 2 h by a bolus of 3) saline or (iv) the ghrelin analog GHRP-2 to overcome feedback inhibition.

Outcome Measures: The impact of age and IGF-I concentrations on GH autofeedback was assessed by regression analysis.

Results: Percentage feedback inhibition correlated negatively with: 1) age after consecutive rh GH/saline infusion (R2 = 0.42, P = 0.005) at any IGF-I concentration; and 2) total IGF-I concentrations after rh GH/GHRP-2 infusion (R2 = 0.40, P = 0.009) at any age. In contrast, sex-steroid concentrations and body mass index were unrelated to degree of autoinhibition.

Conclusions: Increased age in healthy men predicts impaired GH autofeedback, which may contribute to attenuated renewal of high-amplitude GH pulses. Conversely, higher IGF-I concentrations in young men forecast accentuated GH autoinhibition, which may drive prominent GH pulses.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GH PRODUCTION and IGF-I concentrations decline by more than 50% in healthy older adults (1, 2, 3, 4, 5). From a mechanistic perspective, aging selectively reduces the amount of GH secreted in each burst without decreasing the number of bursts or the half-life of GH (6, 7, 8, 9). Young adult-like GH secretory responses are evoked in elderly volunteers by insulin-induced hypoglycemia and combined infusion of three secretagogues (10, 11). By inference, therefore, somatotrope secretory capacity remains intact, but the mechanisms that generate high-amplitude GH pulses are impaired in aging individuals (12, 13, 14). Pulsatile GH secretion is important, inasmuch as the majority (>85%) of GH production occurs in bursts (12, 15). Because the size of GH pulses correlates with somatic growth and hepatic actions of this hormone (16, 17), attenuated GH pulsatility in older individuals may contribute to low IGF-I concentrations that accompany low GH concentrations. In support of this thesis, low doses of GH stimulate normal increments in serum IGF-I concentrations in elderly volunteers (18, 19).

In the experimental animal, the generation of large GH pulses requires interactions among GHRH, ghrelin, and somatostatin (SS) under negative-feedback control by GH and IGF-I (20, 21, 22). A pulse of GH autoregulates hypothalamo-pituitary drive in a biphasic manner, resulting in initial inhibition and then disinhibition of ongoing GH secretion (13, 14, 23, 24, 25, 26). For example, increased GH concentrations evoke prompt hypothalamic SS release in vitro and in vivo (27, 28, 29). SS in turn inhibits GHRH secretion, blocks pituitary exocytosis of GH, and sensitizes somatotropes to the next GHRH stimulus (23, 24, 30). Given the physiological role of negative-feedback mechanisms in the renewal of high-amplitude GH pulses, a fundamental question becomes whether the autoinhibitory process is impaired in aging (12, 31, 32, 33, 34).

Elevated systemic IGF-I concentrations also stimulate SS and repress GHRH gene expression in the hypothalamus, thus mimicking negative feedback by GH (28). Physiological IGF-I concentrations exert negative feedback, given that pharmacological reduction of normal plasma IGF-I concentrations by one third in young adults doubles pulsatile GH secretion (35). What remains unknown are how endogenous IGF-I concentrations impact GH autofeedback and whether age affects this potential relationship.

The present study tests the hypotheses that age blunts GH feedback and that circulating IGF-I augments autoinhibition in healthy men. To examine these postulates, a two-part paradigm was used, in which a brief pulse of recombinant human (rh) GH was infused to elevate blood GH concentrations and thereby suppress ongoing GH secretion. During the suppression phase, saline or the ghrelin analog GH-releasing peptide-2 (GHRP-2) was injected to evaluate the reversibility of feedback inhibition. GHRP was used as the stimulus, because GHRP/ghrelin can evoke arcuate-nucleus GHRH release, synergize with available GHRH, and antagonize SS inhibition in both the hypothalamus and pituitary gland (36, 37, 38). The ensemble mechanisms would be expected to relieve GH autofeedback (27, 28, 30, 39, 40). To allow regression analysis, the feedback protocol was performed in 17 healthy men whose ages spanned 19–71 yr and IGF-I concentrations 93–281 µg/liter.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Seventeen healthy community-dwelling men enrolled in and completed all four study sessions. The span of ages was 19–71 yr (with at least two subjects in each decade) and that of body mass index (BMI) 21–33 kg/m2. Ranges were selected to allow regression of GH response on both age and BMI, given that BMI might be a confounding variable (5, 9). Participants provided voluntary written informed consent approved by the Institutional Review Board. The protocol was reviewed by the National Institutes of Health and approved by United States Food and Drug Administration under an investigator-initiated new drug file for sequential iv injection of rh GH and GHRP-2. No subject was receiving psychotropic or other neuroactive medications, anabolic steroids, or glucocorticoids. Some volunteers took multivitamins, acetaminophen, or ophthalmic drops. Inclusion criteria were a clinically unremarkable medical history and physical examination and normal screening laboratory tests of hepatic, renal, endocrine, metabolic, and hematologic function. Exclusion criteria included the following: acute or chronic systemic illness; fasting plasma glucose more than 126 mg/dl, total testosterone concentration less than 350 ng/dl, LH concentration more than 10 IU/liter, FSH concentration more than 15 IU/liter, hematocrit less than 38% or more than 55%, hyperprolactinemia, or hypothyroidism; night-shift work; significant weight change (≥3 kg in 2 wk); BMI less than 20 kg/m2 or more than 35 kg/m2; sleep apnea; and/or failure to provide informed consent.

Protocol design

The design was prospectively randomized, placebo controlled, and double blind. Inpatient infusion sessions (below) were scheduled at least 3 d apart. Volunteers were admitted to the General Clinical Research Center in the evening before study to allow overnight adaptation to the unit. To obviate food-related confounds, participants were given a meal at 1800 h of 70 kcal/kg containing 55% carbohydrate, 15% protein, and 30% fat, before fasting overnight and during sampling. Lights were extinguished at 2300 h. Ambulation to the lavatory was permitted. Vigorous exercise, cigarette use, caffeinated beverages, and daytime sleep were disallowed.

At 0700 h on the morning of study, iv catheters were inserted in contralateral forearm veins, and blood (5 ml) was withdrawn for later assay of serum concentrations of testosterone, estradiol, and IGF-I. As schematized in Fig. 1Go, beginning at 0800 h, blood samples (1 ml) were collected every 10 min for 5 h. At 0801 h, a 6-min (square wave) iv bolus of saline or rh GH (3 µg/kg) was delivered by infusion pump. Two hours later (at 1000 h), a bolus (<1 min) iv pulse of saline or GHRP-2 (1.0 µg/kg) was injected, and sampling was concluded 3 h later (1300 h).



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  		FIG. 1. Study paradigm used to quantitate rh GH-induced feedback inhibition in healthy men. Negative feedback was imposed by iv infusion of a 6-min square-wave pulse of saline or rh GH (3 µg/kg; at 0801 h) in the fasting state, followed in 2 h by bolus iv injection of saline or GHRP-2 (1 µg/kg; at 1000 h). GH secretion was quantitated by sampling blood every 10 min for 5 h (0800–1300 h), ultrasensitive immunochemiluminometric assay, and biexponential deconvolution analysis. The statistical endpoint is the (summed) mass of GH secreted in bursts (micrograms per liter) over the 3-h interval after saline or GHRP-2 injection (see Subjects and Methods).

 
Hormone assays

GH concentrations were measured in duplicate by automated ultrasensitive chemiluminescence assay using 22-kDa rh GH as standard (Nichols Diagnostics Institute, San Juan Capistrano, CA) (5). All samples (n = 124) from any given subject were analyzed together. Sensitivity is 0.005 µg/liter (defined as 3 SD values above the zero-dose tube). Intraassay and interassay coefficients of variation (CVs) were 5.9 and 6.3%, respectively. No values fell below 0.015 µg/liter. Testosterone and estradiol concentrations were quantitated at screening by automated chemiluminescence assay (ACS 180; Bayer, Norwood, MA), as reported previously (9). Total IGF-I concentrations were measured by immunoradiometric assay (Diagnostic Systems Laboratories, Webster, TX). Interassay CVs were 9% at 64 µg/liter and 6.2% at 157 µg/liter, and interassay CVs were 3% at 55 µg/liter and 1.5% at 264 µg/liter.

Deconvolution analysis

Deconvolution analysis was applied to each 5-h GH time series to estimate pulsatile and basal GH secretion (41, 42). Secretory bursts were defined when the calculated mass exceeded zero at P < 0.05 (43, 44). The (median) slow half-life of elimination of GH was estimated from all four studies of each subject, assuming that a rapid-phase half-life of 3.5 min contributes 37% of the decay amplitude (45). The primary endpoint was the summed mass of GH secreted in bursts (micrograms per liter per 3 h) after infusion of saline and each stimulus, namely, stimulated pulsatile GH secretion. Basal GH secreted contributed to less than 12% of total GH secretion and thus was not assessed further.

Statistical analysis

Repeated-measures one-way ANOVA was used to verify feedback by rh GH and stimulation by GHRP-2 in the cohort as a whole (n = 17) (46). Tukey’s test was applied post hoc to contrast means at overall experiment-wise (P < 0.05) (47).

Percentage inhibition was used as the primary endpoint of rh GH-induced negative feedback. Percentage suppression was calculated in each subject as the feedback-induced decrement in pulsatile GH secretion (micrograms per liter per 3 h) divided by uninhibited (saline-infused) pulsatile GH secretion multiplied by 100%. The decrement was defined as the algebraic difference between pulsatile GH secretion estimated after feedback by saline and rh GH. Decrements were calculated separately in relation to stimulation with saline and GHRP-2 during the suppression phase. Percentage inhibition is relevant, because absolute responses to GHRP-2 appear to depend on age, BMI, sex-steroid concentrations, and baseline GH secretion (48, 49, 50, 51).

Bivariate linear regression analysis was applied initially to relate percentage inhibition (dependent variable) to both age and IGF-I concentrations (independent variables) (46). Based on the absence of any significant statistical interaction between age and IGF-I concentrations, subsequent regression analysis was univariate. Exploratory regression assessed the impact of BMI and sex-steroid concentrations on GH responses to negative feedback. The critical value of each regression was penalized as P ≤ 0.0125, given that four interventions were evaluated (47).

Data are presented as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline (5-h mean) concentrations of GH and fasting (0800 h) concentrations of IGF-I, testosterone, and estradiol are summarized in Table 1Go. The absolute range of total IGF-I concentrations was 93–281 µg/liter in the cohort of 17 men. Each IGF-I concentration represented the mean of four measurements (one per session) in that subject.


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  		TABLE 1. Baseline hormone measurements and peak injected GH concentrations in healthy men

 
During saline/saline infusion, basal, pulsatile, and total GH secretion rates averaged 1.2 ± 0.29, 13 ± 3.0, and 14.6 ± 2.9 µg/liter per 5 h, respectively. The GH half-life was 19 ± 0.8 min, and the interpulse interval was 82 ± 6 min. These unstimulated values are congruent with previous independent analyses in healthy men (5, 9, 44).

Estimates of pulsatile GH secretion (micrograms per liter per 3 h) are summarized in Fig. 2Go for each of the four interventions in the combined cohort (n = 17). Sequential infusion of saline/GHRP-2 increased GH secretion by 13-fold over saline/saline (P < 0.001), rh GH/saline decreased GH secretion by 65 ± 8.1% compared with saline/saline (P < 0.01), and rh GH/GHRP-2 reduced GH secretion by 33 ± 5.9% compared with saline/GHRP-2 (P < 0.05). The difference between 65 and 33% inhibition was significant at P < 0.025. Regression analyses showed that GHRP-2 efficacy correlated negatively with age and BMI after saline infusion (P = 0.023 and P = 0.005, respectively) and after rh GH injection (P = 0.037, age; P = 0.011, BMI) (Fig. 3Go).



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  		FIG. 2. Summed mass of GH (micrograms/liter per 3 h) secreted in the absence (saline) and presence of rh GH-induced negative feedback, followed by stimulation with saline or GHRP-2 in healthy men (Fig. 1Go). Different alphabetic superscripts denote significantly different means by repeated-measures ANOVA. Data are the mean ± SEM (n = 17).

 


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  		FIG. 3. Linear regression plots depicting the negative relationships between GHRP-2 efficacy (GH secretory-burst mass) and age and BMI after saline infusion (top) and after rh GH infusion (bottom). Data are from 17 men. P values reflect univariate estimates.

 
Figure 4Go illustrates individual GH concentration profiles based on sampling blood every 10 min for 5 h in one young (age 22 yr), middle-aged (36 yr), and older man (67 yr). Visual inspection indicated that pulsatile GH secretion falls with age, GHRP-2 stimulates GH secretion less in older individuals, rh GH induces negative feedback, and GHRP-2 partially opposes autoinhibition.



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  		FIG. 4. Illustrative GH concentration profiles in one young (age 22 yr), middle-aged (age 36 yr), and older (age 67 yr) man (rows, top to bottom), each studied on four different mornings fasting (columns, left to right). The four sessions comprised consecutive iv infusion of saline/saline, saline/GHRP-2, rh GH/saline, or rh GH/GHRP-2 (Fig. 1Go). Data reflect sampling every 10 min for 5 h beginning at 0800 h clock time (0 min on x-axis).

 
Bivariate linear regression analysis was used to test the hypothesis that percentage feedback inhibition of saline- or GHRP-2-stimulated GH secretion (dependent variable) is determined by age and IGF-I concentrations (independent variables). Evaluation of partial P values indicated that age and IGF-I concentrations determine percentage feedback independently. Therefore, univariate regression was applied in additional analyses. The results indicated, first, that age correlates negatively with percentage feedback inhibition of unstimulated GH secretion by rh GH (R2 = 0.42; P = 0.007) (Fig. 5Go, top). IGF-I concentrations did not have this relationship. Second, IGF-I concentrations (but not age) correlated positively with percentage feedback inhibition of the GHRP-2 stimulus by rh GH (R2 = 0.40; P = 0.009) (Fig. 5Go, bottom). Exploratory regression analyses revealed that neither BMI nor sex-steroid concentrations correlated with percentage inhibition by rh GH.



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  		FIG. 5. Linear regression of percentage feedback inhibition of pulsatile GH secretion by rh GH on age and IGF-I concentrations. Data are shown in relation to stimulation with saline (top) or GHRP-2 (bottom). R2 values denote the fraction of interindividual response variability (y-axis) attributable to differences in age or IGF-I concentrations (x-axis) in the cohort of 17 men. P values are unadjusted as stated but are interpreted as significant for P < 0.0125 (see Subjects and Methods).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The accompanying analyses indicate that age and IGF-I concentrations are strong reciprocal determinants of GH autonegative feedback in healthy men. In particular, increasing age predicted less feedback inhibition of GH secretion independently of IGF-I concentrations. In contradistinction, higher IGF-I concentrations forecast greater feedback suppression of GHRP-2-stimulated GH secretion independently of age. In contrast, BMI and sex-steroid concentrations were unrelated to degree of autoinhibition. If cycles of GH autoinhibition are crucial to evoke large pulses (13, 14, 25, 26, 38), then impaired negative feedback in older individuals may contribute to their attenuated renewal of GH pulses. Conversely, potentiation of negative feedback in the presence of higher IGF-I concentrations is consistent with more effective GH-pulse generation.

A primary outcome was that age independently of IGF-I concentrations explained 42% of intersubject variability in the negative-feedback action of rh GH on fasting GH secretion. Specifically, negative feedback was reduced remarkably in older individuals, such that median inhibition in men aged less than 25 yr and more than 65 yr was 88 and 34%, respectively. In mechanistic terms, the effect of age could be mediated via a reduced capability of elevated GH concentrations to stimulate SS release and/or repress GHRH output, because GH feedback requires both increased SS and decreased GHRH secretion (12). Because GH negative feedback is transduced via cognate receptors in the brain (28), a possible molecular basis for impaired autoinhibition is decreased central nervous system expression of the GH-receptor gene in older adults, as inferred in postmortem studies (52).

A second salient finding was that IGF-I concentrations independently of age accounted statistically for 40% of the variability in feedback inhibition of GHRP-2-stimulated GH secretion. GHRP/ghrelin is a mechanistically unique agonist that stimulates stomatotropes directly, synergizes with available GHRH, evokes arcuate-nucleus GHRH release, and opposes hypothalamo-pituitary inhibition by SS (37, 53). Higher IGF-I concentrations presumptively antagonize one or more of these actions of GHRP. Pertinent to interpreting this outcome is the fact that an iv pulse of rh GH (3 µg/kg) produced mean peak GH concentrations of 32 µg/liter, which did not vary with age. Peak GH concentrations of 30 µg/liter occur during fasting, during sleep, and in response to exercise in healthy young men (15, 43, 54, 55). A dose-response analysis revealed that a 3.3-fold higher dose of rh GH is required to suppress pulsatile GH secretion maximally in young adults (56). Therefore, the amount of rh GH infused here would not be expected to evoke maximal SS release or inhibit GHRH secretion fully (12). If this reasoning is valid, then the capability of higher plasma IGF-I concentrations to potentiate negative feedback by a pulse of rh GH suggests that circulating IGF-I can augment SS and/or inhibit GHRH outflow (14, 25, 26, 38). Although IGF-I can decrease GH secretion by somatotropes directly in vitro (57), whether systemic IGF-I exerts this particular effect in the human is not established.

The accompanying data corroborate a marked decline in maximal stimulation by GHRP-2 in aging in the absence of an exogenous feedback signal (R2 = 0.36). Recent feedback model-based predictions are that attenuation of GHRP/ghrelin action would impede the recovery of GH secretory bursts after a cycle of autofeedback (38). In support of this postulate, transgenetic muting of neuronal ghrelin/GHRP-receptor gene expression in mice reduces pulsatile GH secretion (21). Therefore, the observed age-dependent decline in the absolute stimulatory effect of saline/GHRP-2 suggests an additional mechanism for attenuated renewal of GH pulses (38).

Qualifications include the cross-sectional nature of observations, which would require comparable longitudinal investigations to verify. The cohort size, albeit relatively small (n = 17 subjects), provided good statistical power for the primary outcomes, namely, power more than 90% to detect an effect of age or IGF-I contributing 35% of the variance in the regression slope at P < 0.05. Conversely, multivariate assessments would require larger groups of volunteers. The current data do not distinguish between the hypotheses that IGF-I-dependent potentiation of negative feedback reflects and contributes to the generation of high-amplitude GH pulses in the young adult. We are unaware of additional direct clinical data on this point. Although GHRP-2 and ghrelin both stimulate the type Ia receptor, whether other uncharacterized receptors may mediate distinguishable actions of these agonists is not known.

In summary, the present study reveals that aging is marked by relative failure of feedback inhibition of pulsatile GH secretion independently of IGF-I concentrations. Conversely, higher IGF-I concentrations forecast greater feedback suppression of GHRP-2-stimulated GH secretion by rh GH independently of age. Assuming that cycles of reversible GH autoinhibition contribute to the generation of high-amplitude GH pulses, the collective outcomes provide new insights into the possible bases of attenuated pulsatile GH secretion in healthy older men and amplified pulsatile GH secretion in young individuals.


   Acknowledgments
 
We thank Dr. Stacey M. Anderson, who was reimbursed to screen, see, and inject some of the study subjects. We are grateful to Kris Nunez for manuscript preparation, Dr. Peter O’Brien for statistical advice (Department of Statistics, Mayo Medical School, Rochester, MN), and Kaken Pharmaceutical Co. (Tokyo, Japan) for supplying GHRP-2.


   Footnotes
 
This work was supported in part by the National Center for Research Resources and National Institutes of Health via General Clinical Research Center Grants M01 RR00847, RR00585, and RO1 AG19695.

First Published Online April 5, 2005

Abbreviations: BMI, Body mass index; CV, coefficient of variation; rh, recombinant human; SS, somatostatin.

Received February 16, 2005.

Accepted March 25, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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