Contribution of growth hormone-releasing hormone and somatostatin to decreased growth hormone secretion in elderly men.

OBJECTIVE: The pathophysiology of the decline in circulating growth hormone (GH) concentrations that may occur with ageing remains elusive. We have investigated the potential contributions of decreased endogenous GH-releasing hormone (GHRH) and increased somatostatin secretion to this phenomenon. DESIGN AND METHODS: The strategy used was to stimulate GH secretion in 8 young (20-24 years old, body mass index (BMI) 22.8 +/- 2.8 kg/m2) and 8 elderly (68-82 years old, BMI 23.4 +/- 1.6 kg/m2) male subjects on separate occasions by means of: (i) intravenous bolus 0.5 microgram/kg D-Ala2 GHRH(1-29)-NH2 alone; (ii) 0.5 microgram/kg GHRH after pre-treatment with two oral doses of 50 mg atenolol (to inhibit somatostatin secretion); (iii) 1.25 mg oral bromocriptine alone (to increase endogenous GHRH and/or inhibit somatostatin); (iv) 50 mg oral atenolol plus 1.25 mg oral bromocriptine; and (v) 0.5 microgram/kg GHRH after pre-treatment with 1.25 mg oral bromocriptine. RESULTS: The elderly men had a significantly lower peak and area under curve (AUC) GH response to intravenous GHRH when compared with 8 young men (peak 3.1 +/- 1.0 ng/ml v. 21.6 +/- 5.0 ng/ml, AUC 205 +/- 56 ng/ml/min v. 1,315 +/- 295 ng/ml/min, P < 0.05). Pre-treatment with atenolol before GHRH administration produced no significant increase in peak and AUC GH response in both groups, which remained lower in the elderly men than in their young counterparts (peak 5.5 +/- 1.8 ng/ml v. 29.3 +/- 7.0 ng/ml, AUC 327 +/- 90 ng/ml/min v. 2,017 +/- 590 ng/ml/min, P < 0.05). Bromocriptine alone did not cause a significant rise in GH concentration in either elderly or young subjects (peak 3.1 +/- 1.1 v. 8.8 +/- 3.2 ng/ml, P > 0.05). When atenolol was administered before bromocriptine, both groups responded but the elderly subjects had a significantly greater peak and AUC response (peak 3.6 +/- 0.7 v. 10.7 +/- 2.1 ng/ml; AUC 191 +/- 39 v. 533 +/- 125 ng/ml/min, P < 0.05). Bromocriptine given before GHRH failed to potentiate GHRH action on GH release in either group. Of 5 elderly men who underwent further evaluation of GH secretory ability, 2 subjects had GH levels > 10 ng/ml, either basally or after intravenous GHRH. The remaining 3 had an initially impaired GH response to bolus intravenous GHRH. After 100 micrograms GHRH subcutaneously twice daily for up to 2 weeks the GH responses to intravenous bolus GHRH (0.5 microgram/kg) were reassessed. One exhibited a normal response (> 10 ng/ml) after 1 week of daily GHRH treatment, another had a near-normal response after 2 weeks (9.7 ng/ml), while the third still had an impaired response by the end of the 2-week treatment period (3.2 ng/ml). CONCLUSIONS: The restoration of endogenous GH secretion in these elderly subjects by means of GHRH priming, and the failure of manipulation of somatostatinergic tone to restore a normal GH response to GHRH suggests that somatotroph atrophy due to a reduction in endogenous GHRH secretion is the principal cause of the diminished GH secretion with ageing.