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Am J Physiol Endocrinol Metab 293: E769-E775, 2007. First published June 5, 2007; doi:10.1152/ajpendo.00709.2006
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Long-term testosterone supplementation augments overnight growth hormone secretion in healthy older men

Ranganath Muniyappa,1 John D. Sorkin,3,4 Johannes D. Veldhuis,5 S. Mitchell Harman,2,6 Thomas Münzer,2,7 Shalender Bhasin,8 and Marc R. Blackman1,2

1Endocrine Section, Laboratory of Clinical Investigation, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland; 2Endocrine and 3Metabolism Sections, National Institute on Aging, National Institutes of Health; 4Division of Geriatrics and Gerontology, Department of Medicine, Department of Veterans Affairs and Veterans Affairs Medical Center, Baltimore Geriatric Research, Education, and Clinical Center, and the University of Maryland School of Medicine, Division of Gerontology, Baltimore, Maryland; 5Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Clinical Research Center, Rochester, Minnesota; 6Kronos Longevity Research Institute, Phoenix, Arizona; 7Geriatric Medicine and Rehabilitation, Bürgerspital, St. Gallen, Switzerland; and 8Endocrine, Diabetes, and Nutrition Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts

Submitted 22 December 2006 ; accepted in final form 30 May 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Circulating testosterone (T) and GH/IGF-I are diminished in healthy aging men. Short-term administration of high doses of T augments GH secretion in older men. However, effects of long-term, low-dose T supplementation on GH secretion are unknown. Our objective was to evaluate effects of long-term, low-dose T administration on nocturnal GH secretory dynamics and AM concentrations of IGF-I and IGFBP-3 in healthy older men (65–88 yr, n = 34) with low-normal T and IGF-I. In a double-masked, placebo-controlled, randomized study we assessed effects of low-dose T supplementation (100 mg im every 2 wk) for 26 wk on nocturnal GH secretory dynamics [8 PM to 8 AM, Q20 min sampling, analyzed by multiparameter deconvolution and approximate entropy (ApEn) algorithms]. The results were that T administration increased serum total T by 33% (P = 0.004) and E2 by 31% (P = 0.009) and decreased SHBG by 17% (P = 0.002) vs. placebo. T supplementation increased nocturnal integrated GH concentrations by 60% (P = 0.02) and pulsatile GH secretion by 79% (P = 0.05), primarily due to a twofold increase in GH secretory burst mass (P = 0.02) and a 1.9-fold increase in basal GH secretion rate (P = 0.05) vs. placebo. There were no significant changes in GH burst frequency or orderliness of GH release (ApEn). IGF-I levels increased by 22% (P = 0.02), with no significant change in IGFBP-3 levels after T vs. placebo. We conclude that low-dose T supplementation for 26 wk increases spontaneous nocturnal GH secretion and morning serum IGF-I concentrations in healthy older men.

pulsatility; testosterone replacement; aging

AGING IN HEALTHY MEN is associated with progressive declines in circulating concentrations of total testosterone (T) and free T and in growth hormone (GH) secretion and IGF-I levels (8, 17). Concomitant with these hormonal changes, there are decrements in skeletal muscle mass and strength (sarcopenia) and bone mass (osteopenia), increases in visceral adiposity, and reductions in physical fitness (18, 19, 31, 35, 36). These undesirable changes in body composition and function may be precursors of major health problems for the older population, including musculoskeletal frailty, bone fractures, insulin resistance, and dyslipidemia, with consequent increased risk of type 2 diabetes and cardiovascular disease (16, 19, 23). Age-related reductions in serum T concentrations are associated with declines in spontaneous GH secretion in men (14, 21, 46). In addition, T administration increases GH-IGF-I axis activity in hypogonadal, but not eugonadal, men (5, 10, 13, 24–26, 40, 47). Thus, it has been proposed that the age-related decline in T secretion in healthy men contributes to the observed reduction in GH secretion and that the hyposomatotropism accompanying the latter may be reversed, at least in part, by T administration (3).

In healthy older men, short-term administration of high doses of T has been reported to augment GH secretion (6, 11, 45). Results from these studies (32) have led some to conclude that low androgen availability may not be a proximate mediator of hyposomatotropism in older men. To date, however, we are unaware of reports of the effects of long-term, low-dose T on GH secretion. In the present study, we report the effects of 26 wk of low-dose T replacement on nocturnal spontaneous GH secretory dynamics, and AM IGF-I and IGF-binding protein (IGFBP)-3 concentrations, in healthy older men with baseline low-normal to mildly decreased T and IGF-I levels.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Study subjects and design. The data reported in this paper derive from a subgroup of men who participated in a larger, 26-wk, two-by-two factorial, randomized, double-masked, double-dummy, placebo-controlled, noncrossover clinical trial of sex steroid and GH replacement in healthy older men and women (4). In the larger study, subjects received either 1) a double placebo, 2) GH alone plus sex steroid placebo, 3) sex steroid alone (T in men, estrogen in women) plus placebo GH, or 4) GH plus sex steroid. In the present report, we compare data from those men who received a double placebo (neither T nor GH) with results from men who received T plus placebo GH. Of the 72 men who participated in the larger study, 68 underwent the overnight frequent GH sampling procedure described below. Of the 68 men, only the subset (n = 34) that received T plus placebo GH (n = 18) or double placebo, i.e., neither T nor GH (n = 16), are reported herein. None of the men had taken any prior T replacement or other medications known to interfere with the gonadal or GH axes. All male study participants were selected to have age-related reductions (1 SD below the mean for values in healthy men, 20–35 yr old) of their circulating IGF-I levels (230 µg/l) and of serum T levels of 470 ng/dl or lower (normal range, 270–1,190 ng/dl) (4). All men were advised to maintain their usual levels of physical activity and to consume their customary diets during the 26-wk protocol. Written informed consent was obtained from each participant. The study protocol was approved by the Institutional Review Board of the Johns Hopkins Bayview Medical Center.

Study design. At baseline, before initiation of T or placebo administration, study participants were admitted to the General Clinical Research Center of the Johns Hopkins Bayview Medical Center at ~08:00 (clock time) on day 1. Body weight and height were measured using a calibrated scale and stadiometer, respectively, and body mass index (BMI; kg/m2) was determined. Meals were served between 1200 and 1300 and between 1700 and 1800. At 1900, an intravenous catheter was inserted into a forearm vein and kept open with heparinized (1,000 U/l) 0.9% sodium chloride. From 2000 to 0800, blood samples (2 ml) were collected at 20-min intervals for GH determinations. Subjects were encouraged to sleep beginning at 2300, and room lights were turned off from 0000 to 0700, but sleep was not monitored. At 0800 on the morning of day 2, after an overnight fast, blood was collected for measurements of T, estradiol (E2), sex hormone-binding globulin (SHBG), IGF-I, and IGFBP-3, and participants were discharged.

Beginning in week 1, a research nurse not involved in the assessment of end points or adverse effects administered T to men as biweekly intramuscular injections of 100 mg of T enanthate (Delatestryl Injection; Bio-Technology General, East Brunswick, NJ) or the same volume of sterile saline placebo. Serum concentrations of T were measured 7 days after the intramuscular T injections throughout the study. All sera were stored at –80°C until assayed.

At week 26, 1 wk following the last T injection, the participants were readmitted for repeat nocturnal blood sampling and early AM hormone measurements identical to those at the baseline visit.

Assays. Total T concentration was measured using a sensitive RIA (38) that has been validated against liquid chromatography tandem mass spectrometry, widely considered the gold standard (7). The sensitivity, defined as hormone concentration corresponding to the 90% B/B0 point, was 0.22 ng/dl (0.008 nmol/l). Intra- and interassay coefficients of variation (CVs) were 13.2 and 8.2%, respectively. SHBG was measured by coated tube immunoradiometric assay (IRMA; Diagnostic Systems Laboratories, Webster, TX) with a sensitivity of 5 nmol/l, with intra- and interassay CVs of 6.7 and 5.0%, respectively. Serum E2 was measured by two-dimensional HPLC with mass spectrometry detection after liquid-liquid extraction (Esoterix, Calabasas Hills, CA). The sensitivity of the assay was 2 pg/ml. Intra-assay and interassay CVs ranged from 1.8 to 3.4% and 3.3 to 4.8%, respectively. GH was measured by IRMA (Nichols Institute Diagnostics, San Juan Capistrano, CA) as previously described (15). The sensitivity of the GH IRMA was 0.05 µg/l. Intra-assay CVs and interassay CVs were 1.7 and 2.7%, respectively. Total serum IGF-I was measured by RIA after acid-ethanol extraction (Esoterix/Endocrine Sciences Laboratories). Sensitivity of the IGF-I assay was 30 µg/l, and the intra- and interassay CVs were, respectively, 5.9 and 7.3%. IGFBP-3 was measured using a polyclonal antibody directed against the binding subunit (Endocrine Science Laboratories). Sensitivity of the IGFBP-3 assay was 0.3 ng/ml, with intra- and interassay CVs of 2.7 and 7.5%, respectively.

Analysis of hormone secretion. GH secretory profiles were assessed using deconvolution analysis as previously described (15). A preliminary fit of the data by a waveform-independent deconvolution methodology (PULSE2) was followed by a multiparameter deconvolution methodology (44). The following secretory parameters were characterized: secretory burst frequency (number of secretory peaks over the 12-h sampling period), mean burst amplitude (average of calculated maximal rates of secretion for all secretory episodes), mass/burst (average amount of hormone secreted/burst), pulsatile production rate, and integrated 12-h concentrations. Basal secretion rates were determined for GH by inclusion of nonzero GH secretion (basal). Ten percent of all GH values fell below the limit of detection of the GH IRMA, and these were assigned a value of 0.025 µg/l with an SD of 0.025.

Approximate entropy. We calculated the approximate entropy (ApEn) of each individual subject's GH concentration-time series. ApEn measures the regularity or orderliness of hormone release, with a higher ApEn reflecting a more random or disordered pattern of hormone secretion (33).

Abdominal MRI. Because older men with age-related decreases in GH and T concentrations often exhibit an increased percentage of abdominal visceral fat (36), and because GH secretion is negatively related to abdominal fat (41), abdominal fat distribution was assessed as previously reported (30).

Statistical analysis. Data were analyzed with SAS version 9.12 (SAS Institute, Cary, NC). Initial data review included visual inspection of Q-Q plots, stem and leaf plots, and box plots. On the basis of initial data review, four extreme (>3 SDs from the mean) data points, two basal GH secretion values (>4.5 SDs from the mean), one total GH production rate value (>5 SDs from the mean) at 26-wk, and one basal GH secretion value (>4.5 SDs from the mean) at baseline were noted. When these values were included in initial analyses, they resulted in extreme studentized residuals (>3.8 SDs). In addition, one total T value at 26 wk resulted in a studentized residual of 3.2 SDs. Extreme values were checked to make sure they were not the result of assay, data recording, or entry errors. We report results from analyses that exclude these observations. When needed, the data were log transformed to achieve a more normal distribution prior to formal statistical analyses. Means and confidence intervals (CIs) were calculated from the log-transformed data, as appropriate, and were subsequently back transformed (by taking the antilog of the values), resulting in geometric means and corresponding 95% CIs. Baseline relationships between GH secretory parameters, IGF-I levels, total T, and abdominal fat content were assessed by correlation coefficients. The magnitude of the change (26-wk value – baseline value) in the group that received T vs. change in the group that received a sex steroid placebo was compared using analysis of covariance (ANCOVA). The dependent variables in the ANCOVAs were the changes (post-pre) in values of the outcome variable being studied. Independent variables included the subject's age, percent change in visceral fat (by MRI), the initial value of the outcome variable, and treatment group (T or placebo). A negative association between the amount of visceral adipose tissue and GH secretion has been demonstrated previously (41), and therefore, significance of changes (26-wk – baseline values) in GH secretory parameters and AM IGF-I levels were adjusted for any proportional change in abdominal fat content due to time or T intervention. Repeated-measures ANCOVA was used to predict log IGF-I concentration across time. Three correlation structures, unstructured, compound symmetry, and first-order autoregressive, were used to control for the serial autocorrelation of repeated observations from the same individual. Akaike's Information Criterion and Schwarz Bayesian Criterion were used to select among the correlation structures. If group-by-time interaction was significant, within-group time point comparisons were made. A P value of <0.05 (2-tailed) was considered significant.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
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 REFERENCES
 
The baseline characteristics of the study subjects are shown in Table 1. There were no significant differences in age, BMI, absolute or percent abdominal visceral fat (by MRI), or AM concentrations of total T, SHBG, E2, IGF-I, or IGFBP-3 between the study participants randomized to receive T vs. placebo (P > 0.20). At baseline, GH mass per burst (r = –0.44, P = 0.01), amplitude (r = –0.45, P = 0.01), pulsatile production rate (r = –0.46, P = 0.008), and integrated concentration (r = –0.55, P = 0.001), but not burst frequency, basal secretion, or half-life, were inversely related to the amount of visceral adipose tissue as assessed by abdominal MRI.


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  		Table 1. Anthropometric and hormonal characteristics at baseline and after 26 wk of T administration in healthy older men

 
At baseline, there was an inverse relationship between AM IGF-I concentrations and visceral adipose fat mass of borderline significance (r = –0.34, P = 0.06). There were no significant relationships between any of the GH deconvolution parameters or IGF-I levels and total T concentration or age (data not shown). Administration of T for 26 wk increased total T by 33% (P = 0.004), into the midnormal range [601 ng/dl (normal range, 270–1,190 ng/dl)], and decreased SHBG by 17% (P = 0.002) compared with men treated with placebo (Table 1). Mean serum E2 levels were 31% higher in men treated with T compared with placebo (P = 0.009; Table 1). There were no significant changes in BMI or absolute or relative amounts of abdominal visceral fat in either the T intervention or placebo groups (Table 1). This was consistent with our prior reports that there were no significant changes in total body fat (absolute or relative) (4) or abdominal visceral fat (30) after T vs. placebo intervention.

At baseline, none of the measured GH secretory parameters differed significantly between the placebo vs. T treatment groups (P > 0.10; Table 2). After T supplementation, nocturnal 12-h integrated GH concentrations increased significantly (Fig. 1 and Table 2). T increased pulsatile GH secretion, due primarily to an increased mass of GH per burst, with an increase in pulse amplitude but not burst frequency, and also to an increase in basal (time-invariant) secretion rate. T did not significantly change orderliness of GH release as measured by a regularity statistic, ApEn (Table 2).


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  		Table 2. GH deconvolution parameters at baseline and after 26 wk of T administration in healthy older men

 

Figure 1
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  		Fig. 1. Twelve-hour nocturnal profile of plasma growth hormone (GH; means ± SE) at baseline ({circ}) and at the end of 26 wk (bullet) in healthy elderly men receiving either placebo or testosterone.

 
T administration increased AM IGF-I concentrations by 22% (P = 0.02, vs. placebo), with no significant change in IGFBP-3 levels (Table 1). As previously reported, in the larger study, analyses (repeated-measures ANOVA) of the sequential changes of IGF-I levels in subjects receiving either placebo, GH alone, T alone, or GH plus T revealed that GH or GH plus T, but not T alone, significantly increased IGF-I levels over time (Fig. 2 in Ref. 4). However, in the present report, post hoc reanalysis with repeated-measures ANCOVA was used to predict the log of IGF-I values across time in men who received placebo alone or T alone. In the present ANCOVAs, change in IGF-I value was the dependent variable and independent variables included the subject's age and treatment group (T or placebo). Repeated-measures ANCOVA revealed a significant group-by-time interaction indicating that T increased IGF-I concentration (P < 0.006). In men receiving T, the changes in GH mass per burst (r = 0.59, P = 0.0004), basal secretion rate (r = 0.36, P = 0.05), and integrated nocturnal GH concentration (r = 0.59, P = 0.0005), but not in IGF-I concentrations, were directly related to the change in total T concentrations.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
This study demonstrates that, in healthy older men, 26 wk of low-dose parenteral administration of T increases nocturnal GH-integrated concentrations by augmenting both pulsatile production (secretory burst mass and pulse amplitude) and basal GH secretion and also increases early AM IGF-I concentrations. To our knowledge, this is the first demonstration of enhanced GH and IGF-I production by prolonged (26 wk) supplementation of low-dose T in older men.

Beginning in the third decade, GH secretion in healthy men is reduced by one-half every 7–12 yr; thus, older men typically exhibit a 65–80% reduction in GH secretion compared with that in young men (18–21 yr) (21, 43, 48). In older men who have age-related reductions in serum T concentrations, significant positive correlations have been observed between serum T levels and both spontaneous and GH-releasing hormone (GHRH)-stimulated GH release (9, 14, 46). Administration of T consistently amplifies pulsatile GH production in hypogonadal men and prepubertal boys but not in eugonadal men (5, 10, 11, 13, 24–26, 40, 47). Such observations have led some to posit that hyposomatotropism in older men is partly due to an age-related decline in circulating T levels (3). However, little is known about the effect of T supplementation on the aging somatotropic axis. Prior studies are limited by either the use of a pharmacological replacement dose (11) or a shorter duration of treatment (<6 wk) (6, 32).

Older men with age-associated reductions in GH and T concentrations have been noted to exhibit an increased percentage of abdominal visceral fat and decreased physical fitness (41, 46, 48). In men in the present study, at baseline, spontaneous GH secretion and, to a lesser extent, IGF-I levels were inversely related to the amount of abdominal visceral fat but not to total T concentrations. This finding was consistent even in the larger group of 74 men aged 65–88 yr who exhibited age-related reductions in IGF-I and T levels (3). In comparison, in the men reported herein who received T supplementation, increases in T concentration were significantly and directly related to increments in nocturnal GH mass/burst and mean GH concentration but not to change in IGF-I.

In this study, T was administered as intramuscular injections of 100 mg of T enanthate every 2 wk, and T levels were measured at baseline and 7 days after each of the intramuscular T injections. Prior studies using a similar dose and preparation (39) have shown that mean peak concentrations of serum T were at the upper end of the normal range, 24 h after an intramuscular injection, and by the end of the subsequent week had fallen to the middle of the normal range. Therefore, the T dosage we used was sufficient to increase serum T levels to the midnormal range, with serum T fluctuations well within the normal range. Of note, concentrations of total T achieved in this study were similar to those reported in a recent study (12) using transdermal T (5 mg/daily) in healthy, community-dwelling, older men (65–80 yr). Additionally, we performed our end-of-study (26 wk) frequent blood sampling for nocturnal GH and early AM IGF-I levels 1 wk after the previous T injection, at which time circulating T levels were in the midnormal range. Thus, the effects of T on GH/IGF-I were not due to "supraphysiological" levels of T, such as those usually occurring with higher doses of parenteral T replacement.

T supplementation increased integrated GH concentration and pulsatile GH production primarily by augmenting GH burst mass and in lesser measure basal GH secretion. This effect of T remained after adjustments were made for any change in the proportion of visceral adiposity (relative adiposity) associated with T administration. Of note, our long-term results contrast with those from other studies examining the effect of short-term (3–6 wk) administration of T on GH secretion in older men. In one study examining the effect of T supplementation (transdermal T patch, 5.0 mg/daily) for 4 wk on nocturnal spontaneous GH secretion (every 10-min sampling) in healthy older men (68 ± 2.5 yr) (6), T treatment did not significantly affect mean GH concentrations or IGF-I levels. Similarly, in another study (32), administration of transdermal T (5.0 mg daily) to elderly men (n = 7, age 70 ± 2 yr) for 6 wk restored T levels to normal ranges (for young men) but did not affect overall nocturnal GH output or parameters of GH pulsatility. In a third study (11), low-dose parenteral T (100 mg im weekly for 3 wk) failed to affect spontaneous GH secretion in healthy older men (n = 8, age 60–80 yr). However, in the same study, a pharmacological dose of T (200 mg im weekly for 3 wk) significantly increased 24-h basal and pulsatile GH secretion with a doubling of GH secretory burst mass and IGF-I levels. In contrast, in eugonadal men (20–40 yr), neither low- nor high-dose T administration exerted any effect on basal or pulsatile GH secretion, suggesting an age-dependent modulatory effect of T on the GH-IGF-I axis in men (11).

Although the mechanisms underlying the age-related decline in GH secretion (somatopause) are not entirely clear, excessive somatostatin release and diminished GHRH secretion may play a role (14, 43). Aging is associated with reduced GH secretory burst mass, which contributes significantly (≥85%) to diminished total GH production (20, 22, 46). Pulsatile GH secretion is jointly controlled by GHRH and ghrelin (feedforward) and by somatostatin, GH, and IGF-I (feedback) pathways (14, 43). Given the ensemble nature of GH secretion, the neuroendocrine mechanisms by which T augments GH-IGF-I axis are unclear and likely to be multifactorial. In the present study, T administration augmented GH secretory burst mass and amplitude, which might have resulted from muting the inhibitory effects of somatostatin and IGF-I and/or enhancing release of GH and/or GH secretagogues. In prepubertal boys, T consistently potentiates GH-releasing peptide's stimulation of GH secretion (1, 27). However, in healthy older men, high doses of T have been reported not to amplify the maximal stimulatory effect of simultaneous infusion of L-arginine, GHRH, and GH-releasing peptide on GH release (45). Similar results were observed in hypogonadal men after 24 wk of T replacement therapy (250 mg im every 3 wk) (5). As a consequence, other studies (5, 34) have suggested that the stimulatory action of T may involve promoting GHRH release from the hypothalamus rather than potentiating its action at the level of the pituitary. In addition, T therapy in healthy older men is known to attenuate feedback inhibition by GH and IGF-I (42). In our study, T administration increased E2 concentrations. The stimulatory effects of T replacement may be mediated via the androgen receptor (40) and/or estrogen receptor (13, 28, 29, 47). This study did not seek to delineate the mechanism(s) mediating the T effects on GH secretion, in particular whether T effects were mediated via the androgen receptor, the estrogen receptor, or both. In the absence of use of E2 antagonists, the role of T-derived E2, if any, in mediating the positive effects of T that we observed on GH secretion cannot be ascertained.

T replacement is known to change regional fat distribution (30). In the complete cohort of men in this study, we previously reported that T administration decreased subcutaneous fat by about 7% but did not significantly alter visceral fat (as assessed by MRI) (30). In the present study, all measures of GH secretion and IGF-I were adjusted for any proportional change in abdominal fat content due to time or T intervention. Prior interventional studies examining the effect of T on GH secretion have not accounted for any T-induced changes in abdominal fat distribution. This is of particular relevance, because after T repletion, the GH response to combined stimulation of L-arginine and GHRH has been reported to be negatively related to the amount of abdominal visceral fat and to account for more than 50% of interindividual response variability in older men (45).

Physical fitness is also an important positive predictor of GH secretion (41, 48). In men in our previous study (4), we reported that T administration did not significantly alter aerobic capacity, as assessed by VO2 max testing, or muscle strength. Thus, changes in fitness and strength are not likely to have played a role in the T-induced changes in GH secretion reported herein.

Systematic review of controlled trials of T administration in healthy older men suggests that T supplementation significantly increases lean body mass and reduces fat mass when compared with placebo treatment (37). As reported previously, low-dose T administration for 26 wk in our original cohort of healthy older men led to a marginal increase in lean body mass (LBM), no change in total body fat (absolute or relative), a small but significant decrease in abdominal subcutaneous fat, and no change in abdominal visceral fat (4, 30). Thus, the clinical significance of T-mediated increases in GH secretion and IGF-I levels in this study is uncertain at this time. Of note, however, is that in our previous report (4), the effects of GH plus T on LBM and fat appeared additive, suggesting that the T response may be submaximal at the dose and duration employed in this present study. In that regard, the effects of exogenous T administration on LBM and serum IGF-I levels are known to be dose dependent (2). Future studies with higher doses or prolonged duration are needed to assess the possible role of changes in GH/IGF-I activity in mediating the anabolic effects of T replacement in older men. At present, there is insufficient information regarding the effectiveness, safety, and functional consequences of GH (26) or T (37) administration to warrant their use, outside of clinical trials, in the treatment of age-associated "somatopause" in men.

Our study has several limitations. First, we assessed GH secretion only at baseline and 26 wk; consequently, we might have missed earlier effects of T replacement on GH secretion. This is potentially important because, as we reported in a previous study (4), T concentrations in men peaked between 8 and 10 wk and gradually diminished by 26 wk postinitiation of T replacement. Second, we did not use E2 antagonists; this prevents us from ascertaining the possible role of aromatization-derived E2 in mediating the observed effects of T supplementation. Third, the dose and duration of T intervention may have been inadequate to fully evaluate temporally biphasic or other effects on GH, IGF-I, and IGFBP-3.

In summary, increasing serum T concentrations to the midnormal range with low-dose T administration for 26 wk increases nocturnal, spontaneous, pulsatile GH secretion and morning IGF-I concentrations in healthy older men. These findings support the hypothesis that age-related reductions in T may contribute to the concurrent somatopause. Further studies are warranted to assess the neuroendocrine mechanisms and clinical consequences of prolonged T stimulation of the GH-IGF-I axis in older men.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported in part by the Intramural Research Programs of the National Center for Complementary and Alternative Medicine and National Institute on Aging (NIA); National Institutes of Health Research Grants RO1-AG-11005 (to M. R. Blackman), R01-AG-19695 (to J. D. Veldhuis), and R01-AG-14369 (to S. Bhasin); General Clinical Research Center Grant MO1-RR-02719 from the National Center for Research Resources, Bethesda, Maryland; NIA Claude D. Pepper Older Americans Independence Center Grant P60-AG-12583 at the University of Maryland, Department of Veterans Affairs and Veterans Affairs Medical Center Baltimore Geriatric Research, Education, and Clinical Center; and the National Institute of Diabetes and Digestive and Kidney Diseases Clinical Nutrition Research Unit of Maryland (P30-DK-072488).


   ACKNOWLEDGMENTS
 
We thank the study participants for their extraordinary and unselfish devotion to advancing knowledge of the aging process, the nursing staff of the Johns Hopkins Bayview Medical Center's General Clinical Research Center for their invaluable assistance in the conduct of patient studies, Carol St. Clair for performance of the GH assays, Paula P. Veldhuis for assistance with deconvolution analysis, Drs. Paul Hees and Edward Shapiro for performance and evaluation of the abdominal MRIs, and Drs. Salvatore Alesci and Irini Manoli for their constructive critiques of this manuscript.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. R. Blackman, Washington DC VAMC, Research Service (151), 50 Irving St., Washington, DC 20422 (e-mail: Marc.Blackman{at}va.gov)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 RESULTS
 DISCUSSION
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J. D. Veldhuis and C. Y. Bowers
Determinants of GH-releasing hormone and GH-releasing peptide synergy in men
Am J Physiol Endocrinol Metab, May 1, 2009; 296(5): E1085 - E1092.
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