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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1303
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 3 1613-1617
Copyright © 2005 by The Endocrine Society

Testosterone Blunts Feedback Inhibition of Growth Hormone Secretion by Experimentally Elevated Insulin-Like Growth Factor-I Concentrations

Johannes D. Veldhuis, Stacey M. Anderson, Ali Iranmanesh and Cyril Y. Bowers

Endocrine Research Unit (J.D.V.), Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; Endocrinology (S.M.A.), Internal Medicine, University of Virginia, Charlottesville, Virginia 22908; Endocrine Service (A.I.), Medical Section, Salem Veterans Affairs Medical Center, Salem, Virginia 24153; and Division of Endocrinology and Metabolism (C.Y.B.), Department of Internal Medicine, Tulane Medical School, New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Endocrine Research Unit, Mayo School of Graduate Medical Education, General Clinical Research Center, 200 First Street Southwest, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The present study tests the hypothesis that a high dose of testosterone (Te) drives GH and IGF-I production, in part, by blunting autonegative feedback by the end-product peptide. To this end, we infused saline or recombinant human IGF-I (10 µg/kg·h iv for 6 h) in seven healthy men ages 51–72 yr after administration of placebo (Pl) and Te in randomized order. GH release was quantitated fasting before and after injection of GHRH (1 µg/kg). Statistical analyses disclosed that Te vs. Pl: 1) increased the mean concentration of GH from 0.15 ± 0.045 to 0.48 ± 0.11 µg/liter (P = 0.007) and IGF-I from 108 ± 5.0 to 124 ± 4.1 (P = 0.047) without altering GHRH-induced GH release; 2) elevated the GH nadir from 0.13 ± 0.03 to 0.23 ± 0.06 µg/liter (P < 0.05) in the control session and from 0.06 ± 0.02 to 0.14 ± 0.04 µg/liter (P = 0.038) during IGF-I infusion; 3) augmented GHRH-stimulated GH release from 3.0 ± 0.56 (Pl) to 3.7 ± 0.52 µg/liter (Te) (P < 0.05) during IGF-I infusion; and 4) did not influence estimated IGF-I kinetics.

In summary, supplementation of a high dose of Te in middle-aged and older men attenuates IGF-I feedback-dependent inhibition of nadir and peak GH secretion. Both effects of Te differ from those reported recently for estradiol in postmenopausal women. Accordingly, we postulate that Te and estrogen modulate IGF-I negative feedback differentially.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TESTOSTERONE (Te) STIMULATES production of both GH and IGF-I in hypoandrogenemic men and boys and genotypic females undergoing gender reassignment (1, 2, 3, 4, 5, 6). In contradistinction, estradiol (E2) promotes GH secretion without consistently elevating IGF-I concentrations, unless a synthetic progestin is also present (7). Reduced or unchanged IGF-I concentrations appear to reflect two estrogenic mechanisms: 1) inhibition of hepatic IGF-I synthesis (8); and 2) potentiation of IGF-I-dependent feedback on GH secretion (9). On the other hand, the mechanisms that subserve Te-dependent elevation of GH and IGF-I concentrations are not known (1, 7, 10, 11, 12). This issue is challenging, in that estrogen receptors mediate stimulation of GH secretion by Te in the human (10, 12, 13, 14). At the level of target tissues, Te does not directly increase GH-induced hepatic IGF-I synthesis (1).

Classical principles of negative feedback predict that the Te-stimulated increase in IGF-I concentrations should inhibit GH secretion. For example, infusion of sufficient recombinant human (rh) IGF-I to mimic midpubertal IGF-I concentrations in adults rapidly suppresses GH secretion (9, 15, 16, 17). Conversely, partial (32%) reduction of systemic IGF-I concentrations by administration of a selective GH-receptor antagonist doubles basal and pulsatile GH secretion in young adults (18). And, mutational inactivation of the IGF-I gene increases GH concentrations by 4- to 10-fold in the human and mouse (15, 19).

On the basis of the evidence that physiological and increased IGF-I availability represses GH secretion, we tested the hypothesis that Te acts uniquely to blunt IGF-I-enforced inhibition of GH secretion. If valid, this action could contribute to combined drive of GH and IGF-I production in a Te-enriched milieu. Indirect precedence for this hypothesis is the capability of Te supplementation to relieve GH-dependent negative feedback in healthy middle-aged and older men (20).


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

To study normal individuals with mild physiological reductions in Te and IGF-I availability, we recruited seven healthy community-dwelling men with a mean (±SEM) age of 63 ± 3.2 yr and body mass index of 27 ± 1.3 kg/m2. Volunteers provided written informed consent approved by the local institutional review board. The protocol was authorized by the Food and Drug Administration under an investigator-initiated new drug file. Eligibility required an unremarkable medical history and physical examination, and normal screening measures of hematologic, hepatic, renal, metabolic, and endocrine function. The last included LH, FSH, prolactin, TSH, T4, SHBG, E2, and total Te concentrations (5, 21). Exclusion criteria comprised the following: acute illness or chronic systemic disease; use of prescription medications, other than diuretics, angiotensin-converting enzyme inhibitors, or topical dermatological and ophthalmic preparations; anemia or polycythemia; substance abuse or neuropsychiatric illness; known or suspected cerebrovascular, cardiovascular, peripheral arterial occlusive, or malignant prostatic disease; clinical features of sleep apnea; allergy to peanut oil (Te excipient); and failure to provide written informed consent.

Clinical protocol

Each participant undertook four overnight admissions to the General Clinical Research Center (GCRC) assigned in a prospectively randomized, patient-blinded, within-subject crossover design. Sampling and infusion sessions were conducted in the morning in the fasting state. Volunteers received an im injection of placebo (Pl) or Te (300 mg enanthate ester in oil) 10 d before each scheduled admission. The dose was chosen to ensure combined stimulation of GH and IGF-I production, and thereby test the a priori hypothesis of Te-dependent relief of end-product inhibition (5). Pl vs. Te interventions were separated by more than 6 wk. Thus, individual study duration was 4–6 months.

To limit nutritional confounds, subjects received a standardized evening meal at 1800 h comprising 10 kcal/kg, with a macronutrient composition of 15% protein, 30% fat, and 55% carbohydrate. Participants remained fasting thereafter until 1400 h the next day. Two (contralateral) forearm iv catheters were placed before 0530 h to permit concomitant blood sampling and saline or rh IGF-I infusion. Blood was withdrawn at 0600 h for the subsequent assay of total IGF-I, Te, E2, SHBG, prolactin, LH, and FSH concentrations. Repetitive blood sampling (2 ml) was performed every 10 min for 8 h beginning at 0600 h (Fig. 1Go). An additional sample was obtained each hour for IGF-I assay. Saline was infused iv between 0600 and 0800 h, followed by a (randomly ordered) constant iv infusion of saline (50 ml/h), or the same volume containing rh IGF-I (10 µg/kg·h) for 6 h (0800–1400 h). Four hours after onset of the infusion, a single bolus of a maximally stimulatory dose of GHRH (1 µg/kg) was injected iv to assess pituitary responsiveness. Sampling was stopped 2 h later (at 1400 h). Subjects were provided lunch before discharge from the GCRC. Smoking, vigorous exercise, daytime sleep, and caffeine were disallowed during the admission.



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  		FIG. 1. Schema of clinical protocol. Seven men undertook four prospectively randomized, double-blind, Pl-controlled inpatient infusion studies; viz., two each after im administration of placebo and Te enanthate 10 d earlier. To appraise negative feedback, saline or rh IGF-I (10 µg/kg·h) was infused continuously iv for 6 h in the fasting state (0800–1400 h) after 2 h of baseline sampling (0600–0800 h); GHRH (1 µg/kg bolus) was injected by iv bolus after the first 4 h of infusion (1200 h); and blood samples were collected every 10 min for 8 h concurrently (0600–1400 h). The nadir was the mean of the lowest three consecutive points in the 2-h interval before GHRH injection.

 
Laboratory assays

Fasting serum concentrations of LH, FSH, prolactin, Te, E2, and SHBG were measured by immunoradiometric assay and RIA, as described previously (5, 21). Total IGF-I concentrations were quantitated by RIA after acid-ethanol extraction (Nichols Diagnostic Institute, San Juan Capistrano, CA) (5). GH concentrations were determined in duplicate in each subject in a single batch (49 samples per session x four sessions) by modified ultrasensitive chemiluminescence assay (Nichols Diagnostic Institute), as validated earlier (22). Sensitivity was 0.005 µg/liter 22 kDa rh GH at 3 SD values above (zero-dose) hypopituitary serum. No samples in the present study contained less than 0.020 µg/liter GH. The median coefficient of variation within assay was 5.2%, and between assay 6.8%.

Analytical procedures

The effects of Te and Pl on GH concentrations were assessed in three relevant time windows: 1) on the saline infusion days, over the 6 h before GHRH injection (0600–1200 h); 2) on all 4 d, absolute three-point nadir over the 2 h before the GHRH stimulus (nadir 1000–1200 h); 3) in each session, mean over 2 h after GHRH injection (stimulated 1200–1400 h); and 4) peak GH concentration after GHRH injection. The amount of GH released after GHRH stimulation was also estimated independently by multiple-parameter deconvolution analysis (21, 23). The analysis assumed published biexponential kinetics of GH disappearance (half-lives 3.5 and 20.9 min, partitioned respectively as 0.27 and 0.63 by relative amplitudes of decay) (24).

Nonlinear regression analysis was applied to estimate the asymptotic rate of increase in total IGF-I concentrations monitored by hourly samples during rh IGF-I infusion. The model was an inverse monoexponential function, wherein the half-time of rise is defined by ln 2/rate constant. Curves were analyzed simultaneously to estimate the intervention-specific rate constant and asymptotic plateau IGF-I concentration, under allowance for subject-specific initial (baseline) IGF-I concentrations. Cohort-dependent 95% statistical confidence intervals (CI) were evaluated by a Monte-Carlo procedure.

Statistical analysis

One-way repeated-measures ANOVA was applied to contrast interventional effects of Pl, Te, saline, and rh IGF-I. Data were compared on the natural logarithmic scale to reduce nonuniformity of variance. Post hoc analyses used the Tukey honestly significantly different test at a protected experiment-wise P < 0.05 (25). Data are presented as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
No subjects reported significant adverse events. Electrocardiograms remained normal. Glucose and phosphorus concentrations did not decrease significantly. Brief facial flushing was noted occasionally after GHRH injection.

Table 1Go summarizes mean fasting (0600 h) hormone concentrations. Compared with Pl supplementation, Te suppressed LH, FSH, and SHBG and increased total Te, E2, molar Te/SHBG, and prolactin concentrations.


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  		TABLE 1. Fasting hormone concentrations measured 10 d after Pl and Te administration in healthy men

 
Figure 2Go depicts GH concentration time series determined by sampling every 10 min over 8 h in the four interventional categories. Visual inspection revealed suppression of GH by rh IGF-I infusion and stimulation by GHRH injection. Analytical outcomes are given below.



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  		FIG. 2. GH concentration profiles in four interventional contexts in healthy men ages 51–72 yr. Volunteers underwent blood sampling every 10 min for 2 h before and 6 h during continuous iv infusion of saline (top) and rh IGF-I (bottom) (0600–1400 h). A maximally stimulatory dose of GHRH was injected iv at the time of the arrow. Studies were performed after randomly ordered supplementation with Pl (left) or Te (right) at least 6 wk apart. Values are the mean ± SEM for the cohort (n = 7).

 
Supplementation with Te followed by saline infusion: 1) elevated fasting GH concentrations 3-fold from 0.15 ± 0.045 to 0.48 ± 0.11 µg/liter (P = 0.007) and IGF-I concentrations from 108 ± 5.0 (Pl) to 124 ± 4.1 µg/liter (Te) (P = 0.047) (Table 1Go); 2) increased pre-GHRH injection nadir GH concentrations by 1.8-fold from 0.13 ± 0.03 to 0.23 ± 0.06 µg/liter (P = 0.05) (Fig. 3AGo); and 3) did not affect GHRH-stimulated peak GH concentrations (Fig. 3BGo) or GHRH-stimulated GH secretory-burst mass (Fig. 3CGo).



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  		FIG. 3. Nadir (A) and peak GH concentrations (B) and estimated mass of GH secreted (C) during the 2-h interval before (nadir) and after (peak, mass) bolus iv injection of GHRH (1 µg/kg). Measurements were made during continuous iv infusion of saline or rh IGF-I in the morning fasting 10 d after single im injection of Pl or Te. Data are the mean ± SEM (n = 7 men). The overall interventional P value was determined by repeated-measures ANOVA, and post hoc comparisons were made by Tukey’s test. Means with entirely different (unshared) alphabetic superscripts differ significantly.

 
Exposure to Pl followed by constant iv infusion of rh IGF-I for 6 h: 1) reduced nadir GH concentrations by 50% from 0.13 ± 0.03 to 0.06 ± 0.02 µg/liter (P < 0.025) (Fig. 3AGo); and 2) suppressed GHRH-stimulated peak GH concentrations and the complementary outcome, GH secretory-burst mass (both P < 0.05) (Fig. 3Go, B and/or C).

Administration of Te compared with Pl followed by IGF-I infusion: 1) elevated nadir GH concentrations from 0.06 ± 0.02 to 0.14 ± 0.14 ± 0.04 µg/liter (P = 0.038); and 2) reversed rh inhibition of IGF-I of GHRH stimulation, as defined by both peak GH concentrations and GH secretory-burst mass (both P < 0.05) (Fig. 3Go). Te comparably relieved suppression of IGF-I of basal (nonpulsatile) GH secretion before GHRH injection (1.8-fold increase for Te vs. Pl) and pulsatile GH secretion (1.7-fold increase in burst mass) (both P < 0.05).

Time courses of total IGF-I concentrations are shown in Fig. 4Go. Infusion of rh IGF-I after Pl exposure: 1) drove plateau IGF-I concentrations to 426 ± 46 µg/liter (P < 0.01 vs. saline control of 108 ± 5.0 µg/liter); and 2) increased IGF-I concentrations at an exponential half-time of 568 min (95% CI, 471–714). rh IGF-I infusion after Te administration yielded a comparable plateau IGF-I concentration (409 ± 39 µg/liter) and similar exponential rate of rise of IGF-I concentrations [half-time, 550 min (95% CI, 491–613)].



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  		FIG. 4. Time course of total IGF-I concentrations measured each hour before and during iv infusion of saline (horizontal interrupted lines) and rh IGF-I (ascending continuous curves) in seven men each studied 10 d after im administration of Pl and Te. Numerical values associated with the curvilinear plots are half-times of rising IGF-I concentrations (minutes) with 95% statistical CI (see Subjects and Methods). Values stated below the horizontal lines are mean (±SEM) IGF-I concentrations.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present clinical investigation demonstrates that supplementation of a GH-stimulating dose of Te (5) in healthy middle-aged and older men elevates IGF-I and GH concentrations, opposes rh IGF-I-induced suppression of nadir GH concentrations, and blunts rh IGF-I-enforced inhibition of peak GHRH-stimulated GH release. The last finding was verified by deconvolution analysis of GH secretory-burst mass. In contrast, Te administration at this higher dose did not alter: 1) the maximal stimulatory effect of GHRH in the absence of exogenous IGF-I; or 2) the rate of rise or plateau concentration of infused IGF-I. Thus, we infer that Te administration mutes IGF-I-dependent negative feedback on GH secretion without altering the apparent kinetics of total IGF-I.

A parallel earlier feedback analysis in healthy postmenopausal women disclosed that acute (10 d) administration of E2 paradoxically accentuates rh IGF-I-induced inhibition of GH secretion (9). Thus, in conjunction with the accompanying data, we postulate that exogenous Te and E2 modulate negative feedback by IGF-I in opposite ways in healthy older adults. The precise mechanistic basis for diametric actions of the two primary sex-steroid hormones is not known, but could arise in pituitary and/or hypothalamic loci.

In relation to the pituitary gland, first, an estrogenic milieu increases hypophyseal expression of IGF-I peptide, IGF-I receptor, and IGF binding protein-2 in the rat, sheep, and cow (26, 27). In principle, such adaptations could modulate the capability of systemic IGF-I to inhibit GH synthesis and secretion (28). On the other hand, how Te regulates pituitary IGF-I peptide or receptor and IGF binding protein-2 expression has not been elucidated (1). Second, in the rodent, E2 represses pituitary expression of somatostatin receptor subtype (SSTR)-5 and increases (rat) or decreases (mouse) that of SSTR-2 (29, 30, 31). Both receptor subtypes transduce inhibition of GH release, but little is known about how Te modulates either endpoint. Additional examination of these issues will be informative, because increased somatostatin outflow to the pituitary gland mediates negative feedback by both GH and IGF-I (1, 32). In this regard, E2 supplementation attenuates the inhibitory potency of exogenous somatostatin in women (33), which would be consistent with down-regulation of pituitary SSTR-5 (above). Given that the aromatase enzyme and E2 receptor are expressed in the human anterior pituitary gland, in principle Te could act as an androgen without transformation or as an estrogen after its systemic or in situ aromatization (1, 34).

With respect to hypothalamic mediation of autonegative feedback, GH and IGF-I act via cognate central nervous system receptors to stimulate somatostatin and repress GHRH gene expression in the rodent (32, 35). Estrogens do not modify central nervous system somatostatin synthesis reproducibly, but suppress hypothalamic concentrations of GHRH peptide and mRNA (rat), and either decrease (rat) or increase pituitary GHRH-receptor gene transcripts (mouse) (1, 31). In postmenopausal women, E2 supplementation doubles the potency of GHRH pulses without altering stimulatory efficacy under putative somatostatin withdrawal (36). If this facilitative action is also achieved in men after aromatization of Te, the effect would be to antagonize IGF-I feedback on endogenously maintained GH release, as observed here. In contradistinction to E2, Te induces hypothalamic synthesis of both GHRH and somatostatin in the adult male rat and mouse (1, 37). If the former mechanism applies in the human, then Te-dependent stimulation of hypothalamic GHRH outflow could additionally attenuate autonegative feedback by GH (38, 39). On the other hand, Te-induced somatostatin secretion would augment rather than attenuate GH and IGF-I-induced negative feedback (40, 41).

In the accompanying study, administration of Te elevated prolactin (an estrogenic effect) and depressed SHBG (an androgenic effect) concentrations. These data and other observations indicate that whether Te acts via the E2 or androgen receptor is specific to the target organ (1). For example, Te appears to stimulate GH secretion by way of the E2 receptor, because the estrogen-receptor antagonists, tamoxifen and clomiphene, inhibit Te drive in hypogonadal men and suppress GH secretion in eugonadal young men (12, 13, 14). Conversely, an antiandrogen, flutamide, amplifies GH secretion in normal men, and nonaromatizable androgens, such as 5 {alpha}-dihydrotestosterone and stanozolol, do not affect spontaneous GH release (3, 42). Whether analogous pathway-specific interventions modulate autoinhibition by systemic IGF-I is unknown.

Several interpretative caveats are pertinent. First, the degree to which our inferences apply to the effects of pubertal Te concentrations or androgen replacement in young individuals has not been elucidated. Although the supraphysiological dose of Te used here stimulated both GH and IGF-I production (5), the concentration dependency of the effects of Te has not been clarified. Second, a maximal GHRH stimulus was used to explore GH secretory capacity and thereby probe endogenous somatostatin inhibition (36). Third, although total IGF-I kinetics did not change detectably after Te administration (Fig. 4Go), no clinical studies have defined whether Te modulates the elimination of unbound and selectively protein-bound IGF-I. And, fourth, in one recent analysis in young men and women, IGF-I was more inhibitory in the male. This difference could reflect an impact of age, Te concentrations, and/or total duration of IGF-I exposure (longer in the young-adult study) (43).

In summary, Te supplementation in healthy middle-aged and older men attenuates rh IGF-I-induced feedback on basal and GHRH-stimulated GH secretion without altering the apparent kinetics of infused IGF-I. A simple interpretation of these outcomes is that a higher concentration of Te blunts the putative stimulation of IGF-I of somatostatin release and/or inhibition of GHRH secretion.


   Acknowledgments
 
We thank Kris Nunez for excellent support of manuscript preparation, the GCRC Core Assay Laboratory for performing the immunoassays, and the GCRC nursing staff for conducting the research protocol.


   Footnotes
 
This work was supported in part by Grants MO1 RR00847 and RR00585 to the GCRC of the University of Virginia and Mayo Clinic and Foundation from the National Center for Research Resources (Rockville, MD), a Clinical Associate Physician award under RR00847 (to S.M.A.), and Grant R01 AG 19695 from the National Institutes of Health (Bethesda, MD).

First Published Online December 7, 2004

Abbreviations: CI, Confidence interval; E2, estradiol; Pl, placebo; rh, recombinant human; SSTR, somatostatin receptor subtype; Te, testosterone.

Received July 7, 2004.

Accepted November 23, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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