It is widely accepted that chronic administration of corticoids in man inhibits the GH response to all of the stimuli tested so far. To study the action of corticoids administered acutely, several dexamethasone challenge tests were performed, after which GH levels were measured for 7 h. In eight volunteers, administration of 4 mg dexamethasone (Dex), iv, induced a clear-cut GH release compared with saline administration. The secretion followed an unusual pattern; basal GH levels (1.5 +/- 0.1 micrograms/L) started rising 2 h after Dex injection, reaching a peak of 17.5 +/- 4.4 micrograms/L after 3 or 3.5 h. Peak levels were maintained until 5 h post-Dex and decreased thereafter. Similar data were obtained when Dex was administered to five volunteers at the dose of 8 mg, orally, with a 30-min delay of the GH peak (19.6 +/- 7.9 micrograms/L). To study whether there was a cholinergic input responsible for the Dex action, another group of eight volunteers underwent three Dex tests (4 mg, iv) on three occasions, followed 90 min later by the administration of placebo (control), atropine (0.5 mg, iv), or pyridostigmine (120 mg, orally). The Dex-induced GH peak (20.8 +/- 5.2 micrograms/L) was not significantly increased by pyridostigmine (cholinergic agonist) treatment (24.2 +/- 4.0 micrograms/L). The blockade of muscarinic receptors by atropine induced a delay in the Dex-induced secretory peak, which appeared at 5 h. However, the Dex-atropine GH peak (14.9 +/- 4.1 micrograms/L) was not different from the Dex-placebo one. In conclusion, Dex alone is able to induce a clear-cut GH secretion in man. The stimulus followed a peculiar time pattern, with peaks levels attained 3 h after either iv or oral administration.

In humans, corticoids suppress growth and growth hormone (GH) secretion elicited by a variety of stimuli, while in the rat they potentiate both in vivo and in vitro GH release. To further study this problem, growth-hormone-releasing hormone (GHRH) tests were performed in 6 nonobese Cushing’s syndrome patients and 6 controls. The normal GHRH-induced GH secretion was completely abolished in the Cushing’s syndrome group. To study the action of shorter corticoid exposures, 34 volunteers were subjected to four tests each: placebo treatment (control); dexamethasone (Dex) administration 4 mg i.v., 3 h before; Dex 8 mg p.o., 12 h before, and Dex 22 mg p.o. over the 2 days before the pituitary challenge that was always administered at 0 min (12.00 h). In the first test (n = 9), GHRH (1 µg/kg i.v.) induced a GH peak of 14.5 ± 3.8 ng/ml (control) that was potentiated by Dex 4 mg i.v. administered 3 h before (26.4 ± 6.8 ng/ml). On the contrary, longer Dex treatments suppress GHRH-induced GH values (6.0 ± 1.1 ng/ml after Dex 8 mg and 1.8 ± 0.3 ng/ml after Dex 22 mg). Clonidine administration 300 µg p.o. (n = 7) increased GH secretion with an area under the secretory curve (AUC) of 1,274 ± 236 that was potentiated by Dex 4 mg i.v. given 3 h before clonidine (2,380 ± 489) and reduced by Dex 8 mg, the reduction being significant only after 22 mg Dex(595 ± 47). When arginine 30 g was used as pituitary challenge (n = 6), the GH peak (19.1 ± 4.8 ng/ml) and the AUC (1,318 ± 322) were not significanty altered by Dex 4 mg nor by Dex 8 mg, but clearly reduced after pretreatment with Dex 22 mg (11.1 ± 4.6 ng/ml peak; 635 ± 189 AUC). The action of Dex was rather selective for GH secretion, because it did not alter (n = 6) prolactin, luteinizing hormone and follicle-stimulating hormone stimulated by a combined administration of luteinizing-hormone-releasing hormone and thyrotropin-releasing hormone. In this group, thyrotropin was only altered after the higher (22 mg) Dex treatment. These results showed a dual action of Dex on GH release in man. Short-term treatment potentiated basal and GHRH-stimulated GH secretion. The stimulatory action of corticoids becomes an inhibitory one when longer treatments are employed, suggesting, though not proving, to be mediated by somatostatin release from the hypothalamus.

Hyperthyroidism is associated with increased serum IGF-I levels and marked alterations in the neuroregulation of GH secretion. These changes involve decreased GH responsiveness to GHRH at the pituitary level and, at the hypothalamic level, a lack of suppressive effect of an oral glucose load. The normal inhibitory effect of exogenous GH administration but not of an oral glucose load in hyperthyroid patients suggests that these two feedback signals act through different mechanisms. The lack of effect of a TRH infusion on GH responses to L-arginine in normal and hyperthyroid patients makes an inhibitory role for TRH in GH secretion unlikely, at least in Caucasian subjects.

It is well known that GH responses to GH-releasing hormone (GHRH) show marked interindividual variations in normal subjects, which have been attributed to a variable somatostatinergic tone. Recently, it has been shown that enhancement of cholinergic tone with the acetylcholinesterase inhibitor pyridostigmine (PD), which presumably acts by inhibiting somatostatin release, stimulates basal GH secretion and GH responses to a maximal dose of GHRH. In this study we have investigated the effects of PD on the dose-response relationships of GHRH-induced GH secretion in normal subjects. Our data showed that PD (120 mg, orally, at-60 min) induced a clear-cut increase in basal GH levels, significantly different from that after saline treatment, at 15, 30, 45, 60, 90, and 120 min. Moreover, PD administration markedly potentiated GH responses to GHRH at doses of 500, 100, 25, 10, and 3 micrograms/subject, as assessed by either area under the curve or maximal peak GH levels. In fact, GH responses to pyridostigmine plus 3 micrograms GHRH were similar to those to the administration of 500 and 100 micrograms GHRH alone. Our findings of marked increases in GH response to GHRH after pyridostigmine administration show that with enhancement of cholinergic tone, the dose of GHRH needed to induce a similar increase in GH is reduced 30 times.

Anorexia nervosa is associated with several abnormalities in GH secretion elicited by different stimuli. To investigate the precise mechanism of this alteration, GHRH was administered to 14 women: a group of eight anorexia nervosa patients in the acute phase of their illness and a control group of six age-matched volunteers. As patients with anorexia nervosa have chronic low oestrogen values, the volunteer women of the control group underwent a second GHRH test after pretreatment with the oestrogen receptor blocker tamoxifen. GHRH 1-29 (1 microgram/kg i.v.) induced a GH peak (mean +/- SEM) of 28.2 +/- 5.1 ng/ml (GH ng/ml x 2 = mU/l) at 30 min in the anorectic patients. This value was no different from the GHRH-stimulated GH peak in the control women (28.1 +/- 10.0 ng/ml). Tamoxifen pretreated women had a GH peak after GHRH of 35.6 +/- 9.7 ng/ml, not significant versus control test. Compared with the control group, oestrogen levels were significantly lower in anorectic patients and higher in tamoxifen-treated women. GHRH administration induced a small PRL peak at 15 min that was similar in the three groups tested. After this 15 min peak, PRL in both anorexic and tamoxifen-treated women returned toward basal values steadily. However, in untreated control women a second PRL peak was evident at 60 min. In conclusion, GHRH-induced GH secretion in anorexia nervosa patients was similar to that in control subjects and in controls under oestrogen receptor blockade.