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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 12 6325-6330
Copyright © 2004 by The Endocrine Society

Sustained Growth Hormone (GH) and Insulin-Like Growth Factor I Responses to Prolonged High-Dose Twice-Daily GH-Releasing Hormone Stimulation in Middle-Aged and Older Men

Johannes D. Veldhuis, James T. Patrie, Kirsten Frick, Judith Y. Weltman and Arthur Weltman

Division of Endocrinology and Metabolism, Department of Internal Medicine (J.D.V.), Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; and Departments of Health Evaluation Sciences (J.T.P.), Medicine (J.Y.W., A.W.), and Human Services (A.W.), General Clinical Research Center, School of Medicine (K.F.), University of Virginia Health System, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, 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
 
Postulated mechanisms underlying the relative hyposomato-tropism of aging include reduced hypothalamic drive by GHRH. To test this notion, we administered 1 mg (n = 11) vs. 4 mg (n = 11) recombinant human GHRH-1,44-amide sc twice daily for 3 months in a double-blind, parallel-cohort design to 22 healthy men (ages, 53–68 yr). After 3 months, GHRH elevated: overnight GH concentrations from 0.71 ± 0.19 to 1.74 ± 0.39 µg/liter (P < 0.001; 1 mg) and from 0.80 ± 0.15 to 5.12 ± 0.40 µg/liter (P < 0.001; 4 mg) and IGF-I concentrations from 117 ± 14 to 234 ± 20 µg/liter (P = 0.007; 1 mg) and from 147 ± 13 to 286 ± 22 µg/liter (P < 0.001; 4 mg). Only the higher GHRH dose also increased total body water (tritium space; P = 0.024) and fat-free mass (dual-energy x-ray absorptiometry; P = 0.021), and reduced total abdominal adiposity (computed axial tomography scan; P = 0.042). Both supplementation schedules shortened the time required to walk 30 m and ascend four flights of stairs (P < 0.025 each). Lower extremity strength, aerobic capacity, and bone mineral density did not change. Local injection site reactions were common.

We conclude that sc administration of a large dose of GHRH (4 mg) twice daily for 3 months elevates GH and IGF-I concentrations, increases total body water and fat-free mass, reduces total abdominal adiposity, and enhances certain performance measures in healthy aging men but causes local skin reactions.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
AGING IS ACCOMPANIED by an increased prevalence of features of physical frailty. Signs and symptoms may include sarcopenia and osteopenia, reduced exercise capacity, lower red cell mass, greater visceral adiposity, impaired glucose tolerance, insulin resistance, dyslipidemia, and diminished sense of well-being (1). Adults with organic GH deficiency exhibit comparable signs and symptoms, which are significantly ameliorated or reversed by GH replacement (2).

Extrapolations from cross-sectional data indicate that beginning in young adulthood GH secretion declines by approximately 50% every 7 yr in healthy men (3, 4, 5, 6). Accordingly, compared with 18- to 21-yr-old men, middle-aged and older individuals exhibit a 75% or greater reduction in 24-h integrated GH concentrations. From a regulatory perspective, attenuated GH secretion in mid- and later adulthood may arise (nonexclusively) from decreased stimulation by endogenous GHRH and/or increased inhibition by hypothalamic somatostatin (7, 8). Whether high doses of exogenous GHRH are able to overcome reduced GH and IGF-I production for a sustained interval is not known. In addition, whether the anticipated rise in GH and IGF-I concentrations under effective GHRH stimulation would block continued responsiveness by negative feedback is not clear. The latter issue is particularly pertinent in older individuals, given that aging putatively accentuates somatostatinergic outflow (7, 8).

Several interventional studies in the older human have administered GHRH for up to 21 d (9, 10, 11). None has demonstrated a uniform and sustained elevation of both GH and IGF-I concentrations into the young-adult range. A single investigation was extended to 4 months. This study used once-daily injection of a low dose of GHRH, which induced minimal GH responses restricted to several hours after each injection without elevating IGF-I concentrations (12). To address the foregoing inconsistencies, the present study adopted two revised strategies: administration of high doses of recombinant human (rh) GHRH twice daily (bid) and comparison of responses with rh GHRH stimulation after 1 and 3 months.


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

A total of 22 healthy elderly men participated. Subjects provided written voluntary informed consent approved by the Institutional Review Board. Volunteers were ambulatory, community-dwelling, recreationally active men. Physical characteristics were [mean (range)]: age, 60 (53–68) yr; height, 177 (172–184) cm; and weight, 84 (76–89) kg. At baseline, the two groups did not differ significantly (see Results). Each participant had a normal medical history, physical examination, and screening tests of hepatic, renal, metabolic, hematologic, and endocrine function. Exclusionary criteria were recent weight loss or gain (exceeding 3 kg in 6 wk); acute or chronic systemic disease; psychiatric illness; orthopedic problems that would limit exercise and balance testing; drug or alcohol abuse; administration of psycho- or neuroactive medications; exposure (within 10 biological half-lives) to testosterone, anabolic steroids, or (nontopical) glucocorticoids; anemia (hemoglobin < 13 g/liter); cerebro-, cardio-, or peripheral arteriovascular disease; reluctance to inject peptide bid for 3 months as an outpatient; obstructive uropathy, elevated prostate-specific antigen (>4 µg/liter), or abnormal digital prostatic exam; lack of prompt access to the General Clinical Research Center (GCRC); and unwillingness to provide informed consent.

Clinical protocol

Volunteers were admitted to the GCRC on three occasions to undergo blood sampling overnight and metabolic studies the next day; viz., at baseline, and after 1 and 3 months of intervention (below). Interventions were assigned in a parallel-cohort, prospectively dose-randomized, double-blind fashion as bid sc injection of either 1 (n = 11) or 4 (n = 11) mg GHRH (rh GHRH-1, 44-amide; BioNebraska, Inc., Lincoln, NE). The peptide was administered at 2200 and 0800 h in prefilled (protocol and date-defined but dose-unlabeled) syringes. Peptide was reconstituted and dispensed weekly by the Investigational Drug Pharmacy by dilution in 1 ml bacteriostatic water. Syringes were kept refrigerated. Volunteers continued their usual daily activities, dietary habits, and recreational exercise. The project was approved by the U.S. Food and Drug Administration (Washington, DC) under an investigator-initiated investigative new drug file.

Inpatient studies

To limit confounding by variable nutrient intake, enrollees were admitted to the GCRC in the morning after ingesting a standardized breakfast at home (nutrient composition: 55% carbohydrate, 15% protein, and 30% fat). Thereafter, subjects received compositionally fixed isocaloric meals of 12.5 kcal/kg at 1200 and 1700 h. Individuals remained fasting the next night. At 1800 h, an indwelling iv catheter was placed in an antecubital vein to allow repetitive blood sampling (1.5 ml) every 10 min for 12 h beginning at 2000 h. Vigorous exercise, hypnotics, caffeinated beverages, smoking, and alcohol use were disallowed in the GCRC. Room lights were extinguished at 2300 h.

Functional assessments

Strength and physical performance were quantitated at baseline and after 3 months of intervention. Best effort scores were reported for each subject.

Strength. Isokinetic eccentric and concentric strength of the quadriceps femoris and biceps femoris muscle groups was assessed using the Kin-Com II isokinetic dynamometer (Chattex Corp., Hixson, TN). After familiarization with the procedure, subjects performed three knee flexions and extensions at a calibrated velocity of 60°/sec. To estimate quadriceps strength, the lateral epicondyle of the knee was aligned with the axis of the dynamometer, the inferior edge of the force pad was placed directly superior to the medial malleolus, and Velcro straps were applied across the hips, thigh, and ankle for stabilization. Gravity correction was performed with the knee at 0° flexion (13).

Physical performance. Functional locomotor ability was assessed by a timed stair climb and 30-m walk. Subjects were asked to descend four flights of stairs, wait 1 min, and ascend so quickly as possible using the railing for balance only. The timed 30-m walk was conducted twice on a level unobstructed passageway made with 1 min of rest intervening.

Peak oxygen consumption (VO2 max). Volunteers performed graded bicycle ergometry as outpatients to determine the individual lactate threshold (LT) and VO2 max at baseline and 24–48 h before the 1- and 3-months studies in the GCRC. Initial power output was 20 W, the demand of which was increased by 15 W every 3 min until volitional exhaustion. Forearm venous lactate concentrations were monitored at rest and during the last 15 sec of each power stage (2700 Select Biochemistry Analyzer; Yellow Springs Instruments, Yellow Springs, OH). The LT was taken as the highest power output achieved before onset of the curvilinear increase in lactate concentrations (exceeding at least 0.2 mM) (14). Oxygen consumption was quantitated by open-circuit spirometry (Sensormedics Metabolic Cart 229; Sensormedics, Yorba Linda, CA) and heart rate by electrocardiography (Marquette Max-1). VO2 max was defined as VO2 uptake at voluntary exhaustion.

Body composition analysis

Total body water. Participated received tritiated water (<0.12 mSv) orally at 0900 h on the second morning of study. Blood and urine samples were collected 1, 2, 3, and 4 h later. Equilibrated radioactivity was quantitated by liquid scintillography. The density of water at body temperature was taken as 0.99371 kg/liter (15).

Percentage body fat. For hydrostatic densitometric estimates, subjects were weighed in air on an Accu-weigh beam scale accurate to 0.1 kg and weighed again underwater on a Chatillon autopsy scale accurate to 10 g (16). Residual lung volume was measured by O2 dilution (17). Calculated percentages of total body fat were made as described (15).

Total body bone mineral mass. Dual-energy x-ray absorptiometry (DEXA) was used to estimate fat-free mass (FFM) and bone mineral ash (Hologic QDR-2000, pencil beam mode, enhanced whole-body analysis software version 5.64, Hologic, Waltham, MA). Absorbance was multiplied by 1.279 to estimate total body bone mineral mass. A single trained investigator analyzed all DEXA records (15).

Abdominal visceral fat (AVF). AVF was determined by single-slice computed axial tomography (CT) at 140-kV energy and a 0.5-cm slice thickness at the L4–L5 intervertebral space with no angulation (18) (Picker PQ 5000 and by Voxel Q three-dimensional image processing; Picker International, Cleveland, OH). Subcutaneous fat and AVF were calculated by delineating anatomical landmarks with a mouse-computer interface and computing the cross-sectional area within the absorbance attenuation range, –190 to –30 Hounsfield units (19). Total abdominal fat was the sum of sc and AVF fat in the same frame.

Body composition. The four-compartment model was applied, as described (15, 20).

Hormone assays

Integrated GH concentrations were determined by automated immunochemiluminescence assay of sera collected every 10 min from 2000 to 0800 h overnight (Nichols Diagnostics Institute, San Juan Capistrano, CA) (4, 5). Assay sensitivity (at 3 SD above the zero-dose tube) was 0.005 µg/liter. Median intraassay and interassay coefficients of variation were 5.2 and 8.3%. No values fell less than 0.050 µg/liter in the present study. Fasting (0800 h) serum concentrations of total IGF-I (Nichols Diagnostics Institute) and total and free testosterone and estradiol (Diagnostic Products Inc., Webster, TX) were determined exactly as reported (6).

Statistical methods

Outcomes are reported as the mean ± SEM. Relative responses (fold effects) within subject are given as the geometric mean ratio [and 95% statistical confidence intervals (CI)] of the value observed at 1 or 3 months to that recorded at baseline. Logarithmic transformation was used before statistical analyses to limit dispersion of variance (21). To adjust for within-subject correlations, the model comprised hierarchical mixed-effect two-way analysis of covariance (ANCOVA), wherein the baseline outcome served as the (within-subject) covariate (22). Model specification parameters (two x two factors) were dose (1 vs. 4 mg bid GHRH), duration of intervention (1 and 3 months), and the dose-by-duration interaction (23). The equal-slope assumption of the ANCOVA structure was tested by a generalized F ratio test at P < 0.05, followed by restricted maximum-likelihood estimation of parameters. When the ANCOVA assumption was rejected (P < 0.05), interventional effects were defined as the cohort median (50%) of the corresponding distribution of {delta}-values (intraindividual algebraic difference between the response determined at 1 or 3 months and baseline).

After demonstrating a significant interaction, post hoc comparisons were made subject to experiment-wise type I error rate of less than 0.05 and Fisher’s least significant difference test (22). Computations were performed using PROC MIXED in SAS version 8.0 (SAS Institute Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Figure 1Go summarizes overnight (mean) GH and fasting (0800 h) IGF-I concentrations determined at baseline and after 1 and 3 months of administration of 1 or 4 mg GHRH bid. Both the 1- and 4-mg bid doses elevated concentrations of GH (both P < 0.05) and IGF-I (both P < 0.05) at 1 month. The higher dose increased concentrations of IGF-I further at 3 months compared with 1 month (P = 0.012). The 4-mg bid dose was no more effectual than the 1-mg dose in increasing IGF-I at 1 month but was significantly more effective in increasing GH concentrations at 3 months. Responses to the 4-mg bid dose of GHRH considered separately and expressed as fold-baseline were: for GH, 2.6 (95% CI, 1.9–3.6)-fold at 1 month and 6.4 (4.6–8.7)-fold at 3 months (P = 0.034 for 1 vs. 3 months GH response); and for IGF-I, 1.4 (1.2–1.7)-fold and 2.1 (1.7–2.5)-fold at 1 and 3 months, respectively (P = 0.05 for 1 vs. 3 months IGF-I response).



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  		FIG. 1. Impact of sc administration of rh GHRH-1,44-amide 1 vs. 4 mg bid for 1 and 3 months in a total of 22 healthy middle-aged and elderly men. The left panel gives mean (overnight) GH concentrations and the right panel fasting IGF-I concentrations. Means with entirely different (unshared) alphabetic superscripts differ significantly from one other among the 0-, 1-, and 3-month outcomes; e.g. A and B differ, but BC does not differ from B or C. P values reflect the overall interventional effect. Data are the mean ± SEM (n = 11 subjects per group). The abscissa is deliberately nonordinal for space constraints.

 
Table 1Go summarizes basic measures of body composition. None was affected by GHRH treatment, except for total body water and body weight. In particular, the 4-mg bid dose increased total body water (P = 0.024) (Fig. 2Go, left), and elevated weight (P < 0.001) (Table 1Go). Both peptide doses decreased total (sc plus visceral) abdominal fat estimated within subject; viz., the low dose by 8.7% (95% CI, 1.0–16%; P = 0.032) and the higher dose by 15% (1.0–27%; P = 0.042) [P = not significant (NS) between dose] (Fig. 2Go, right). Only the low dose of GHRH reduced AVF by 17% (1.4–30%) (P = 0.04) and total body fat mass by 2.3 kg (P < 0.05) (Table 1Go). Percentages of total body fat, thigh fat, thigh muscle areas, and bone mineral density did not change in either cohort (Table 1Go). The higher dose of GHRH increased FFM significantly (P < 0.01) (Fig. 3Go).


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  		TABLE 1. Estimates of body composition at baseline and after 3 months of GHRH administration

 


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  		FIG. 2. Significant impact of bid sc administration of 4 mg (but not 1 mg) rh GHRH on total body water content (tritium space) (left) and total abdominal fat area (CT) (right) determined after 3 months of intervention. Data are presented as described in the legend of Fig. 1Go.

 


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  		FIG. 3. Augmentation of FFM by bid sc injection of 4 mg (but not 1 mg) rh GHRH for 3 months. Data are presented as defined in Fig. 1Go.

 
The 1-mg bid dose of GHRH augmented power output (watts) at the LT (data not shown). This may be fortuitous because as shown in Table 2Go, neither dose altered peak power expenditure, maximal O2 consumption, heart rate, blood pressure, and peak lactate concentrations.


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  		TABLE 2. Indices of exercise performance

 
Figure 4Go presents outcomes of tests of physical performance. Administration of either dose of GHRH for 3 months shortened the 30-m walk time and reduced the time required to climb four flights of stairs. Neither GHRH schedule improved muscle strength (Table 3Go).



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  		FIG. 4. rh GHRH supplementation at a dose of either 1 or 4 mg bid for 3 months (but not 1 month) reduces the time (seconds) required to complete a 30-m walk (left) and a four-flight stair climb (right). Data are presented as the mean ± SEM, as defined in the legend of Fig. 1Go.

 

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  		TABLE 3. Estimates of isokinetic strength

 
Safety data

Fasting concentrations of glucose, insulin, glycated hemoglobin, hepatic enzymes, creatinine, and prostate-specific antigen were normal at baseline and did not change significantly at 1 or 3 months.

Untoward events included variable local erythema, pruritus, and a less than 2.5-cm edema at the sc injection site after the first dose of peptide. Comparable injection reactions recurred over the first 2–12 d in five of 11 subjects given GHRH 1 mg bid and over 2–21 d in nine of 11 subjects given 4 mg bid. There were no systemic adverse effects. No volunteer discontinued participation. All subjects completed all evaluations.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study demonstrates that sc administration of a 4-mg dose of rh GHRH-1,44-amide bid in healthy middle-aged and older men increases integrated GH concentrations by 2.6- and 6.4-fold after 1 and 3 months, respectively. Concomitantly, this intensive schedule of GHRH supplementation elevates IGF-I concentrations by 1.4- and 2.1-fold after 1 and 3 months, respectively. The magnitude and durability of the GH and IGF-I responses markedly exceed those reported at any lower dose of GHRH in healthy middle-aged and older subjects (see introductory section). These outcomes demonstrate that a sufficient dose and frequency of exogenous GHRH drive are able to overcome expected systemic negative feedback exerted by rising concentrations of GH and IGF-I (24, 25, 26). In a pathological context, rare ectopic tumoral secretion of GHRH can elevate concentrations of GH and IGF-I excessively (27).

In earlier clinical studies, pulsatile or constant iv or sc infusion of GHRH in postmenopausal women and older men augmented pulsatile GH secretion and IGF-I concentrations over a 1- to 3-d interval (6, 28). Thus, under adequate GHRH drive, GH and IGF-I production may increase rapidly. On the other hand, injection of lower doses of GHRH bid or continuously in healthy elderly men increased GH and IGF-I concentrations minimally after 2–6 wk (9, 10, 11, 29, 30). Moreover, once-daily administration of a low dose of GHRH for 1.5 or 4 months in aging volunteers failed to elevate IGF-I concentrations, alter body composition, or enhance physical performance (12, 30). The present marked (2- to 6-fold) and continuing (1 and 3 months) increases in GH and IGF-I concentrations establish that bid administration of a high dose of GHRH exerts sustained stimulation of the somatotropic axis in middle-aged and older men. Analyses of the effects of two dose strata at the two time points further indicate that the dose and duration of GHRH administration determine outcomes. In particular, only the very high GHRH dose (4 mg bid) induced greater GH secretion after 3 months than 1 month, increased total body water (tritium dilution), augmented FFM (DEXA), and decreased total abdominal fat content (CT scan). Relatively modest body compositional effects would be consistent with the 3-month duration of this investigation.

The current data establish that pituitary and hepatic responses to exogenous GHRH and endogenous GH, respectively, do not wane between 1 and 3 months of continued stimulation with GHRH. Whether partial down-regulation occurs before measurements made at 1 month is not determinable from our data. Continuing efficacy of high doses of GHRH was not always observed in other short-term contexts (31, 32, 33). The basis for the latter contrasting outcome is not well defined. However, from a mechanistic perspective, laboratory experiments reveal that chronic administration of GHRH up-regulates its own receptor in the young rodent; induces pituitary expression of the ghrelin gene in the mature animal; stimulates de novo GH gene transcription in vitro and in vivo; and in transgenic animals induces somatotrope hypertrophy, hyperplasia, and adenomata (9, 10, 11, 34, 35, 36).

By way of study limitations, the lack of a comparison placebo group retested at 1 and 3 months should be noted because there could be a learning effect in performance measures. On the other hand, GHRH dose dependency aids interpretation, and test-retest analyses of GH measurements show high repeatability over consecutive days or weeks (37). From a clinical perspective, skin reactivity to high doses of peptides would limit long-term use in our view. Also, the relatively small effects on body composition and physical performance identified after 3 months should be validated in extended interventional regimens.

In conclusion, an investigative paradigm of bid sc administration of a high dose of GHRH for 3 months in middle-aged and elderly men elevates IGF-I and GH concentrations by 2.1- and 6.4-fold, respectively; increases total body water; augments FFM; reduces total abdominal fat; improves selected measures of physical performance; and imposes local cutaneous but not systemic toxicity. Alternative, more tolerable modes of administration of high doses of GHRH over prolonged intervals will be required to further define the dosimetry, risks, and benefits of GHRH supplementation in selected contexts.


   Acknowledgments
 
We thank Kimberly Coulter and Kris Nunez for excellent assistance in manuscript preparation, the GCRC Core Assay Lab staff for performance of the immunoassays, and the GCRC nursing staff for conducting the research protocol. GHRH peptide was donated by BioNebraska, Inc. under the authors’ investigative new drug file at the U.S. Food and Drug Administration.


   Footnotes
 
This work was supported in part by Grants MO1 RR00847 and RR00585 to the General Clinical Research Centers of the University of Virginia and Mayo Clinic and Foundation from the National Center for Research Resources (Rockville, MD) and by Grant R01 AG 19695 from the National Institutes of Health (Bethesda, MD).

Abbreviations: ANCOVA, Analysis of covariance; AVF, abdominal visceral fat; bid, twice daily; CI, confidence interval(s); CT, computed axial tomography; DEXA, dual-energy x-ray absorptiometry; FFM, fat-free mass; GCRC, General Clinical Research Center; LT, lactate threshold; NS, not significant; rh, recombinant human; VO2 max, peak oxygen consumption.

Received March 2, 2004.

Accepted August 19, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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