Age-related differences in growth hormone (GH) regulation during strenuous exercise.

This study was designed to investigate the central neuroendocrine mechanisms by which exercise (EX) stimulates growth hormone (GH) release as a function of age. Twelve male subjects, six in their early-to-mid twenties and six in their late sixties or seventies, received a strong GH stimulus either as incremental EX until volitional exhaustion or by administration of GHRH alone or Hex alone two hours after a presumed maximal GH response to combined administration of GHRH plus hexarelin (Hex). Total GH availability was calculated as area under the curve (AUC) over time periods 0 - 120 and 120 - 240 min. The mean AUC in micro g/l x 120 min to GHRH+Hex in the younger group was approximately twice that in the older group (11,260, range 3,947 - 19,007 vs. 5,366, range 2,262 - 8,654). In younger males, the mean AUC to EX (509, range 0 - 1,151) was larger than to GHRH (119, range 0 - 543), but less than that to Hex (919, range 0 - 1,892). In the older group, GH responses to EX and GHRH were abolished (mean AUC: 112, range 0 - 285, and 156, range 30 - 493), respectively) in contrast to the response to Hex (1,077, range 189 - 1,780). These data indicate that maximal GH stimulation by GHRH+Hex results in greater desensitization of GHRH compared to Hex, irrespective of age. We postulate that the abolished responsiveness of GH to EX in older group is due to insufficient disinhibition of hypothalamic somatostatin activity and desensitization of GHRH, while the preserved activity of a central Hex-related pathway is not involved. The GH response to EX in younger males is due to complete inhibition of somatostatin activity and stimulation of a central Hex-related pathway in spite of GHRH desensitization. We conclude that a central Hex-related pathway is the primary factor for EX-induced GH release only in younger males.

Involvement of endogenous growth hormone-releasing hormone (GHRH) in the exercise-related response of growth hormone.

The aim of this study was to investigate the involvement of endogenous growth hormone-releasing hormone (GHRH) in the growth hormone (GH) release during strenuous exercise (EX). Eight healthy male subjects (age: 22.1 +/- 0.8 yr, body mass index: 22.2 +/- 0.9 kg/m 2, .VO 2 max: 52.2 +/- 0.5 ml/min/kg [mean +/- SEM]) were exposed to incremental EX until volitional exhaustion (cycle ergometry), and in random order to a maximally stimulating bolus injection of 100 microg GHRH, or to combined administration of 100 microg GHRH and EX (GHRH+EX). Serial blood samples in the fasted state were taken immediately before the start of each trial, and at appropriate intervals over 2 h. Total GH availability was calculated as area under the response curve (AUC), corrected for differences in baseline values. The results showed that peak serum GH levels to GHRH alone and EX alone were not significantly different: 41.5 +/- 9.0 microg/l and 64.1 +/- 8.1(mean +/- SEM). Peak GH level to GHRH+EX was 156.1 +/- 19.9 microg/l, which was significantly greater than to either stimulus alone (p < 0.02) or additively (105.6 +/- 17.1 microg/l, p < 0.02). AUC's to GHRH alone and EX alone were not significantly different (3242 +/- 839 vs. 2472 +/- 408 microg/l x 120 min). AUC to GHRH+EX (7807 +/- 1221 microg/l x 120 min) was greater than to either stimulus alone (p < 0.02) or additively (5714 +/- 1247 microg/l x 120 min, p < 0.02). This indicates a potentiating (synergistic) effect between GHRH and EX. We postulate that GH responses to strenuous EX are only partially due to maximal GHRH activation. Next to complete inhibition of hypothalamic somatostatin activity, which is achieved by strenuous exercise, activation of endogenous GH-releasing peptides, such as Ghrelin, must be operative.

Relationship between circulating levels of sex hormones and insulin-like growth factor-1 and fluid intelligence in older men.

The relationship was investigated between baseline serum levels of total testosterone (T), free testosterone (FT), dehydroepiandrosterone sulfate (DHEAS), ESTRADIOL (E2), sex hormone-binding globulin (SHBG), insulin-like growth factor-1 (IGF-1) and cognitive functioning in 25 healthy older men (mean age 69.1 years). Cognitive tests concerned measures not sensitive to ageing (crystallized intelligence), and measures sensitive to ageing (fluid intelligence and verbal long-term memory). Partial correlation coefficients (controlled for level of education) revealed significant associations of total T (r = -.52, p = -.009), SHBG (r - .59, p = .002) and IGF-1 (r = .54, p = .007) with the composite measure of fluid intelligence test performance, but not with crystallized intelligence, nor verbal long-term memory. Stepwise hierarchical regression analysis with the composite measure of fluid intelligence as the dependent variable showed that the contributions of SHBG, total T, and IGF-1 were not additive.

Intersubject responsiveness of high-affinity growth hormone (GH)-binding protein (GHBP) to long-term GH replacement therapy.

In adult growth hormone deficiency (GHD) syndrome responsiveness to GH replacement therapy is reported to vary considerably. The underlying mechanisms, however, are not well understood. The aim of this study was to investigate which baseline variables determine the reported variable intersubject responsiveness of high-affinity GH-binding protein (GHBP) to GH replacement therapy. In the setting of a double blind study over 12 months with placebo control over the first 6 months, we analyzed the interrelationship between a number of baseline variables, which vary considerably amongst subjects, and the GHBP response to GH replacement in 31 GHD adults (21 males and 10 females). The following variables were investigated: age, gender, duration of GHD, body composition, serum levels of high-affinity GHBP, insulin-like growth factor-1 (IGF-1), and IGF-binding protein-3 (IGFBP-3). The results showed that in the 6 months treated group of 16 patients (11 males, 5 females), serum IGF-1 increased from 87 ng/ml (range: 26 to 173) to 250 (range: 62 to 467) (p<0.01) and GHBP increased from 1,302 pmol/l (range: 845 to 1,m960) to 1418 (range: 941 to 2,025) (p=0.04). Both parameters showed a significant time effect (within-subjects) (p<0.001). In the 12 months treated group of 15 patients (10 males, 5 females), serum IGF-1 increased from 92 ng/ml (range: 20 to 180) to 272 (range: 45 to 491) (p<0.01), whereas GHBP did not show a significant change: from 1,186 pmol/l (range: 660 to 1,690) to 1,252 (range: 580 to 1,890) (p=0.87). Also no significant time effect (within-subjects) was observed for GHBP (p=0.06). Step-wise multiple regression analyses revealed that during the 6 months placebo period baseline GHBP explained 83% of the variance in post-placebo GHBP, whereas the variance in post-treatment GHBP could be accurately predicted (adjusted R2=0.93) from baseline GHBP and body fat mass, irrespective of the duration of GH treatment. No other baseline variables contributed independently to the GHBP response, with the exception of IGFBP-3, which showed a small, but significant contribution in females, but not in males. These findings indicate that the variable intersubject responsiveness of GHBP to GH replacement therapy is mainly due to differences in baseline body fat mass amongst adult GHD patients, and that in female patients a relatively low baseline IGFBP-3 contributes to a rise in serum GHBP after GH treatment. The clinical relevance of measuring GHBP in adult GHD patients is limited to the first screening step to diagnose GHD, because long-term GH therapy tends to restore serum GHBP to pretreatment levels.