Lack of desensitization of adenomatous somatotrophs to growth-hormone releasing hormone in acromegaly

The study was undertaken to investigate whether GHRH causes desensitization in GH-secreting adenomas in analogy to the normal situation. For this purpose, GH secretion after repeated GHRH administration to acromegalic patients in vivo and cultured adenomatous somatotrophics in vitro was studied. Six acromegalic patients and 6 normal subjects received 3 consecutive 50 μg GHRH rapid iv injections at 2-h intervals. Blood samples were drawn at 0, 15, 30, 60, and 120 min after each dose. The acromegalic patients had variable responses to the first injection and in each patient the second and third injections elicited serum GH responses that were quite similar to those after the first one. The GH increment, evaluated as net incremental area under the curve (mean ± SE; nanograms per ml/120 min) was 2660 ± 1501 after the first injection, 2176 ± 1378 after the second injection, and 1978 ± 1191 after the third injection; P = NS. On the contrary, in normal subjects a marked elevation of GH was observed only after the first injection (net incremental area under the curve, mean ± SE after the first injection: 710 ± 154; after the second injection: 6 ± 39 and after the third injection: 108 ± 28, P <0.01 vs. the first dose). The effect of in vitro GHRH pretreatment on the subsequent response to GHRH was evaluated in monolayer cultures from 12 GH-secreting adenomas. At 10^-8 M, GHRH significantly stimulated GH release from 8 adenomas. The GHRH pretreatment that was effective in inducing desensitization in cultured rat anterior pituitary cells, i.e. preexposure of the cultured cells to 10^-8 M GHRH for 4 h at 37 C, did not abolish the GH response to the subsequent challenge with GHRH (mean percent stimulation: 150 ± 14% in untreated cells vs. 153 ± 30% in pretreated cells; P = NS). Only in one adenoma did GHRH-promoted desensitization occur. No modification was found in GHRH unresponsive adenomas. In the adenomas, not only the efficacy but also the potency of GHRH on GH release after GHRH pretreatment was of the same order of magnitude as in untreated cells. No desensitization to GHRH action occurred when the pretreatment time was prolonged up to 8 h and the GHRH concentration in the preincubation medium was increased to 10^-7 M. In conclusion, the in vivo and in vitro data reported here indicate that in acromegaly GH response to GHRH persists in spite of the continuous presence of GHRH and that this secretory behavior can be at least in part attributed to an impairment of the desensitization process.