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Short-Term Testosterone Supplementation Relieves Growth Hormone Autonegative Feedback in Men

Division of Endocrinology and Metabolism (J.D.V.), Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; Division of Endocrinology (W.S.E., A.L.W.), Department of Internal Medicine, Department of Obstetrics and Gynecology (W.S.E.), General Clinical Research Center, and Department of Human Services (A.L.W.), School of Education, General Clinical Research Center, University of Virginia Health System, Charlottesville, Virginia 22908; Research and Development Office (A.I.), Salem Veterans Affairs Medical Center, Salem, Virginia 24153; and Department of Internal Medicine (C.Y.B.), Division of Endocrinology and Metabolism, Tulane Medical School, New Orleans, Louisiana 70112-2699

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

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The present study tests the postulate that testosterone (Te) stimulates GH secretion, in part, by attenuating autonegative feedback. To this end, 13 healthy men (ages 43–71 yr) received three consecutive weekly im injections of placebo (Pl) (n = 7) or Te (200 mg) (n = 6) in a prospectively randomized, double-blind, parallel-cohort design. An iv pulse of saline or recombinant human (rh)GH (3 µg/kg·6 min) was infused 2 h before bolus saline or GH-releasing peptide (GHRP)-2 (1 µg/kg) in the fasting state. Blood was withdrawn every 10 min, GH concentrations were quantitated by chemiluminometry, secretion was determined by deconvolution analysis, and outcomes were compared by ANOVA. After Pl, rhGH suppressed basal, pulsatile, and GHRP-2-stimulated GH secretion by 2.6-, 2.4-, and 2.1-fold, respectively (each P < 0.03), and truncated GHRP-2-stimulated GH secretory bursts (P < 0.005). Compared with Pl, Te: 1) stimulated basal and pulsatile GH secretion by 1.9 and 2.4-fold (P < 0.01 and P < 0.02), respectively; 2) reduced feedback on basal GH secretion (P < 0.01); 3) blunted GHRP-2-stimulation by 1.9-fold (P < 0.01); and 4) facilitated initial recovery of rhGH-suppressed GH concentrations (P < 0.005). The foregoing actions were selective, inasmuch as Te did not relieve autoinhibition of pulsatile GH secretion.

In summary, short-term Te supplementation decreases rhGH-imposed negative feedback on basal GH secretion and enhances early escape of GH from autoinhibition. In principle, such actions could potentiate the renewal of high-amplitude pulses of GH in androgen-replete individuals.

	Introduction

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ELEVATED GH CONCENTRATIONS stimulate somatostatin and repress GHRH secretion, thereby mediating autoinhibition (1, 2, 3). Mathematical models predict that rapid and reversible negative feedback drives high-amplitude GH pulses (4, 5). In a recent clinical study, sex steroid-replete pubertal boys evinced greater fractional suppression by exogenous GH than prepubertal controls or young men (6). Estradiol supplementation in postmenopausal women did not alter autofeedback on pulsatile GH secretion but muted inhibition of GH-releasing peptide (GHRP)-2 stimulation (7). In contrast, how testosterone (Te) administration affects GH autofeedback in men is not known. This question is meritorious, because Te replacement in androgen-deficient boys and men amplifies pulsatile GH secretion by 2-fold (8, 9, 10). Elevated GH concentrations would be expected to repress continued GH secretion by autofeedback actions. A plausible explanatory hypothesis is that Te blunts autonegative feedback. The present study examines this postulate in normal middle-aged and older men.

	Subjects and Methods

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Subjects

Thirteen healthy men enrolled in and completed all four study sessions. The range of ages was 47–67 yr [placebo (Pl), n = 7] and 43–71 y (Te, n = 6) (P, not significant). The body mass index was 24–30 kg/m². Participants provided written voluntary informed consent approved by the Institutional Review Board, National Institutes of Health, and United States Food and Drug Administration under an investigator-initiated new drug file for the experimental sequential iv injection of recombinant human (rh)GH and GHRP-2. No subject was receiving psychotropic or other neuroactive medications, anabolic steroids, or glucocorticoids. Some volunteers took multivitamins, ferrous sulfate, calcium carbonate, acetaminophen, or ophthalmic drops. Inclusion criteria required a clinically unremarkable complete medical history and physical examination and normal screening laboratory tests of hepatic, renal, endocrine, metabolic, and hematologic function (hematocrit > 38%). Exclusion criteria included acute or chronic organic illness; known or suspected ischemic cardiac, peripheral arterial or cerebrovascular disease; fasting plasma glucose more than 120 mg/dl; morning total serum Te concentration less than 280 ng/dl; LH concentration more than 15 IU/liter; FSH concentration more than 20 IU/liter; hematocrit less than 38% or more thyan 55%; hyperprolactinemia or hypothyroidism; recent transmeridian travel (exceeding three time zones within the prior week); night-shift work or significant weight change (3 kg in 2 wk); allergy to peanut oil; systemic anticoagulation; sleep apnea; substance abuse; and/or failure to provide informed consent.

Protocol design

The design was a prospectively randomized, Pl-controlled, double-blind, parallel-cohort intervention comprising supplementation with Pl (1 ml saline) or Te (200 mg enanthate ester) injected im weekly for 3 consecutive weeks (designated d 1, 8, and 15). Inpatient infusion sessions (below) were scheduled during the inclusive time window encompassing d 10–21 after the first injection (d 1). Individual sessions were separated by a minimum of 48 h.

Volunteers were admitted to the General Clinical Research Center (GCRC), on each of four randomly ordered occasions, the evening before study to allow overnight adaptation to the Unit. To obviate food-related confounds, participants were given a constant evening meal (turkey sandwich or vegetarian alternative) of 500 kcal containing 55% carbohydrate, 15% protein, and 30% fat at 1800 h, and then remained fasting overnight and the next morning until noon. Lights were extinguished at 2300 h. Ambulation to the lavatory was permitted. Vigorous exercise, caffeinated beverages, and daytime sleep were disallowed. Lunch was provided before discharge from the GCRC.

As schematized in Fig. 1, at 0600 h on the morning of study, two iv catheters were inserted in contralateral forearm veins. Blood (5 ml) was withdrawn at 0700 h for later assay of serum concentrations of LH, FSH, Te, estradiol, and IGF-I. Thereafter, blood samples (2 ml) were collected every 10 min for 5 h (from 0700 h to 1200 h). Immediately after the first sample was withdrawn at 0700 h, a 6-min (squarewave) bolus of saline or rhGH (3 µg/kg) was delivered iv by Harvard infusion pump. A bolus (<1-min) pulse of saline or GHRP-2 (1.0 µg/kg) was injected iv 2 h later (at 0900 h). Blood samples were withdrawn for 3 additional hours to monitor GH release.

View larger version (16K): [in this window] [in a new window]   FIG. 1. Schema of paradigm of GH autofeedback. Subjects received consecutive iv injections of: 1) saline or rhGH (3 µg/kg pulse over 6 min); and 2) saline or GHRP-2 (1 µg/kg bolus) 120 min later. Blood sampling extended every 10 min for 5 h.

Serum GH concentrations were measured in each 10-min sample in duplicate by automated ultrasensitive chemiluminescence assay using 22-kDa rhGH as assay standard (Nichols Institute Diagnostics, San Clemente, CA) (11, 12). Samples (n = 124) from any given set of four admissions were analyzed together. Sensitivity of the modified GH assay is 0.005 µg/liter (defined as 3 SDs above the zero-dose tube); and median intra- and interassay coefficients of variation (CVs) are 5.2% and 6.3%, respectively, at the GH concentrations measured here. No sample values fell below 0.020 µg/liter. LH and FSH concentrations were quantitated by automated chemiluminescence assay (ACS 180, Bayer, Norwood, MA) using the First and Second International Reference Preparations, respectively, as standards (13). Corresponding sensitivities are 0.5 and 2.0 IU/liter; intraassay CVs, 6.3 and 7.4%; and interassay CVs, 6.5 and 8.5%. Te and estradiol were quantitated by solid-phase RIA with sensitivities of 20 ng/dl (0.69 nmol/liter) and 10 pg/ml (35 pmol/liter) and within-assay CVs of 6.4% and 8.2%, respectively (Coat-A-Count, Diagnostic Products, Los Angeles, CA) (14). Total serum IGF-I concentrations were measured by RIA after extraction in acid-ethanol (Nichols Institute Diagnostics). The assay threshold is 30 µg/liter, and intra- and interassay CVs are 5.3% and 6.2%, respectively (6, 7).

Analysis of pulsatile GH secretion

The half-life of decay of infused rhGH (1000–1200 h) was quantitated by multiparameter deconvolution analysis of the corresponding 2-h serum GH concentration profile, assuming a biexponential GH elimination process (15, 16). The latter was represented by a rapid-phase half-life of 3.5 min, a slow-phase half-life estimated analytically in each subject, and a nominal fractional (slow/total) decay amplitude of 0.63 (17). Endogenous GH secretion during saline/saline infusion was determined over the full 5-h window (0700–1200 h). Deconvolution analysis was applied analogously in all sessions over the 3-h interval (0900 h-1200 h) after bolus saline or GHRP-2 injection. The outcome measures are pulsatile GH release (the summed mass of GH secreted above basal), basal (nonpulsatile) secretion, and total (combined basal and pulsatile) GH production (given as µg/liter·6 h during baseline saline/saline infusion and as µg/liter·3 h after bolus saline/GHRP-2 injection). Intervention-specific GH secretory-burst asymmetry (analytically defined skewness term) was reconstructed by fitting all data sets in each cohort simultaneously, as described (18). The skewness term quantitates relative departure from time symmetry of the upstroke and downstroke of a secretory burst at any given half-duration; i.e. quantitates relative rates of ascent and descent within a burst (19). Positive skewness is represented by a mean and one-sided 95% confidence intervals that do not overlap zero. This outcome signifies significant prolongation of the descending, compared with ascending, phase of the secretory burst.

Statistical analysis

Measures of GH secretion were analyzed statistically on the natural logarithmic scale as a variance-stabilizing procedure (20). Three-way nested ANOVA in a 2 x 2 x 2 factorial design was applied to establish an interaction among Pl/Te, saline/rhGH, and saline/GHRP-2 administration in determining 3-h basal and pulsatile GH secretion. Two-way ANOVA within intervention (Pl or Te) was used to examine the interactive effects of rhGH and GHRP-2 on GH secretion. Post hoc comparisons were made via Tukey’s honestly significantly different criterion at an overall (experiment-wise) type I error rate of 0.05 (21).

Numerical values in the text and tables are presented as the mean ± SEM (median) or 95% statistical confidence intervals for GH secretory-burst symmetry.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Statistical analyses of fasting (baseline) hormone measurements revealed that Te supplementation, compared with Pl, significantly increased serum concentrations of (6-h mean) GH and (0700 h) IGF-I, Te, and estradiol and decreased those of LH and FSH (Table 1).

View larger version (32K): [in this window] [in a new window]   FIG. 2. GH concentration time series in healthy middle-aged and older men randomly assigned to receive three weekly injections of either Pl (A) or Te (B). Data reflect the four study conditions highlighted in Fig. 1. Arrows depict the timing of iv infusion of saline/rhGH (open arrow at 10 min) followed by saline/GHRP-2 (solid arrow at 130 min). Data are the mean ± SEM (n = 7 Pl, n = 6 Te). Note the expanded y-axis scale in insets under rhGH feedback (left bottom subpanels).

View larger version (21K): [in this window] [in a new window]   FIG. 3. Impact of Pl (solid bar) or Te (hatched bar) administration on saline vs. rhGH-enforced autonegative feedback on basal (A) and pulsatile (B) GH secretion (µg/liter·unit time) in healthy men. Data are presented as the mean ± SEM. P values were determined by ANOVA. Means marked by unshared (entirely different) alphabetic superscripts differ significantly.

View larger version (23K): [in this window] [in a new window]   FIG. 4. Effect of Pl and Te supplementation on saline (left) and rhGH-induced (right) feedback inhibition of the mass (A) and skewness (B) of GH secretory bursts stimulated by bolus iv injection of GHRP-2. Positive skewness reflects a longer duration of the descending than ascending phase of the calculated GH secretory burst. C, Stability of slow-phase half-life of secreted GH (left) and injected rhGH (right) (top panel), and total duration of induced GH secretory bursts (bottom panel). Data are the cohort mean and 95% statistical confidence intervals (A and B) and the mean ± SEM (C). Differing superscripts (A–C) denote significant mean contrasts. NS (not significant) denotes P > 0.05.

Figure 5A presents the time course of recovery of mean GH concentrations after the rhGH-induced nadir (point of maximal inhibition in the absence of GHRP-2 stimulation). Linear regression analysis revealed that the mean slope (rate of recovery x 10^-4), over the time window 210–270 min after the iv GH pulse, was significantly negative at -5.4 ± 2.4 (±SD, P < 0.25) in the Pl setting, but positive at 87 ± 24 (P < 0.005) in the Te-replete context. Figure 5B depicts absolute nadir serum GH concentrations (µg/liter) enforced by a pulse of rhGH, which were 3.3-fold higher after Te than Pl supplementation (P < 0.01). If extrapolated to a 24-h secretion rate (assuming a 7% distribution volume), the nadir increment under Te corresponds to approximately 22–38 µg/d basal GH release or about 8–17% of total daily GH secretion.

View larger version (18K): [in this window] [in a new window]   FIG. 5. Te reverses the slope of time-dependent early recovery of GH concentrations after autoinhibition (A), and increases nadir GH concentrations without altering their timing (B). Numerical values are the mean and 95% confidence intervals for the cohort slope estimate (A) or the mean ± SEM (B).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

View larger version (26K): [in this window] [in a new window]   FIG. 6. Summary of observed outcomes of Te repletion and rhGH-induced feedback on basal, pulsatile, and GHRP-2-stimulated GH secretion in 13 middle-aged and older men. SS, Somatostatin.

Te administration stimulates pulsatile and total daily GH secretion by 2-fold (9, 10). Albeit not definitive, correlational data suggest that high-amplitude GH pulses are important for optimal linear growth in puberty (26, 27, 28). In the present study, Te supplementation augmented the mass of GH secreted in bursts by 2.4-fold. Te did not impede feedback inhibition of unstimulated pulsatile GH secretion, but significantly blunted stimulation by GHRP-2 (Fig. 6). Mechanistically, nonaromatizable androgens stimulate hypothalamic somatostatin gene expression in the adult rodent (1, 2). If relevant in the human, androgen-induced somatostatinergic restraint could provide a plausible basis for inhibition of GHRP-2 stimulation by Te in men. On the other hand, one study reported that Te administration in prepubertal boys enhances the action of a synthetic GHRP (29). This evident difference could reflect an age-related or developmental contrast, the eugonadal vis-à-vis hypogonadal baseline state, and/or a type I statistical artifact in either analysis. Thus, further study of this point will be important.

Te repletion, but not Pl, reversed the decline in GH concentrations 4 h after controlled feedback imposition (Fig. 6). Specifically, Te exposure elicited significant recovery (positive slope) of suppressed GH concentrations 3 h after the rhGH feedback signal. More rapid initial escape from autoinhibition also occurs in Te-sufficient midpubertal, compared with prepubertal, boys (6). The precise mechanisms that mediate postfeedback recovery of endogenous GH secretion in the human have not been established. However, the repressive phase of negative feedback proceeds via acutely increased somatostatin and decreased GHRH release (see introductory paragraph of this manuscript). Recovery putatively entails gradual reduction of somatostatinergic outflow. In the latter regard, experiments in the conscious ram show that abatement of somatostatinergic inhibition triggers rebound-like hypothalamic release of GHRH and pituitary secretion of accumulated GH stores (30). Based upon reciprocal regulation of somatostatin and GHRH signals during rebound-like GH secretion, we reason that Te may enhance initial escape from GH autofeedback by suppressing somatostatin and/or heightening GHRH release.

In summary, short-term Te supplementation in healthy middle-aged and older men attenuates experimentally induced feedback inhibition of basal GH secretion and enhances the initial rate of recovery of suppressed GH concentrations. Further investigations will be required to elucidate how each dynamic mechanism impacts effectual renewal of high-amplitude GH pulses in Te-replete individuals.

	Acknowledgments

 
We thank Jean Plote for excellent assistance in manuscript preparation, Ginger Bauler and Brenda Grisso for performance of the immunoassays, and Sandra Jackson and associated nursing staff for conducting the research protocol.

Dr. Stacey Anderson saw patients and gave injections on a fee-for-service basis.

	Footnotes

 
This work was supported, in part, by MO1 RR00847 and RR00585 (to the GCRCs of the University of Virginia and Mayo Clinic) from the National Center for Research Resources (Rockville, MD), and R01 AG-19695 (to J.D.V.) from the National Institutes of Health (Bethesda, MD).

Abbreviations: CV, Coefficient of variation; GCRC, General Clinical Research Center; GHRP, GH-releasing peptide; Pl, placebo; rh, recombinant human; Te, testosterone.

Received June 11, 2003.

Accepted November 17, 2003.

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