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Fig. 3. Mean (± SD) plasma levels of GH during the continuous intravenous infusion of saline (left) or of GHRH, 1 ^g/Kg/h (right), for 24 h in 6 healthy young men. Infusions were preceded and followed by bolus injections of GHRH, 1 ^g/Kg iv. There is an increase in GH secretion during GHRH infusions, but in an episodic pattern, with periods of higher GH occurring at approximately the same time as during saline infusions. The response to GHRH injections is unaltered following saline infusions but decreased after GHRH infusions, showing attenuation of the response or depletion of releasable GH stores. From ref. 9.

the magnitude of this was much less than that seen with GnRH and did not lead to a similar paradoxical inhibition of pituitary secretion. Also, even with sustained high levels of GHRH in the tumor patients, GH secretion remained pulsatile, as discussed above in Physiologic Responses. This provided early evidence that chronic treatment with GHRH could increase GH production as long as the pituitary was intact; that long-acting agonists, when they were developed, would behave primarily as agonists; and that it was not necessary to provide a pulsatile pattern of GHRH stimulation in order to elicit a pulsatile response.

Assays for GHRH were developed rapidly and showed that plasma GHRH levels in the tumor-bearing index patients were in the range of 1 ng/mL or higher. A survey of nearly 200 samples collected from patients with acromegaly at several centers showed low levels in all but the index patients, suggesting that ectopic overproduction of GHRH is an uncommon cause of acromegaly (15). Several additional cases of ectopic GHRH syndrome have since been identified, many of them identified by the other hormone overproduction syndromes seen in patients with pancreatic adenomas, carcinoid tumors, or small-cell carcinomas of the lung; but the general finding of this early study has held up. The incidence is sufficiently low that it is still debated whether a measurement of the plasma GHRH level is a cost-effective part of the initial evaluation of patients with acromegaly.

Although the general view is that the great majority of patients with low circulating levels of GHRH have autonomous GH-producing pituitary adenomas, it is possible that some of these patients have hypothalamic ("eutopic") rather than ectopic GHRH overproduction. These patients would presumably have somatotroph hyperplasia rather than adenomas, and would respond to GHRH antagonists with a reduction in GH secretion, as do normals and patients with ectopic GHRH secretion (16,17). Although most observers believe that this situation is also a rare one, the frequency of eutopic overproduction of GHRH has not yet been characterized.

Fig. 4. Growth hormone (GH) responses (± SEM) to the intravenous bolus injection of 1 pg/Kg GHRH in groups of normal (NL) prepubertal boys and girls, in children with idiopathic short stature (ISS), and in children with either idiopathic (IGHD) or organic (OGHD) GH deficiency. The number of subjects in each group is shown in parentheses. *,p < 0.05 vs normal, and IGHD vs OGHD. From ref. 21.

Fig. 4. Growth hormone (GH) responses (± SEM) to the intravenous bolus injection of 1 pg/Kg GHRH in groups of normal (NL) prepubertal boys and girls, in children with idiopathic short stature (ISS), and in children with either idiopathic (IGHD) or organic (OGHD) GH deficiency. The number of subjects in each group is shown in parentheses. *,p < 0.05 vs normal, and IGHD vs OGHD. From ref. 21.

GHRH injections or infusions stimulate a further rise in GH secretion even in acromegalic patients with presumed pituitary adenomas (18). Since responses of the normal somatotrophs are blunted by the high levels of IGF-1, this has been taken as evidence that most somatotroph adenomas are sufficiently well differentiated to retain GHRH receptors linked to GH responses. It has been suggested that cytotoxic agents such as ricin A chain or boron-containing compounds could be linked to GHRH analogs to ablate these tumors selectively (19), but this potential therapeutic approach has not reached clinical trials.

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