SUPPRESSED SPONTANEOUS AND STIMULATED GROWTH-HORMONE SECRETION IN PATIENTS WITH CUSHINGS-DISEASE BEFORE AND AFTER SURGICAL CURE

Growth retardation to complete growth arrest is the hallmark of Cushing's syndrome in children. The major mechanism for this has been considered the glucocorticoid-induced resistance of target tissues to insulin-like growth factor-I (IGF-I) and other growth factors. The purpose of this study was to examine the GH secretory dynamics of patients with Cushing's disease before and up to 12 months after their cure by transsphenoidal adenomectomy. In 14 patients, blood sampling every 20 min over 24 h for determination of plasma GH was performed before and 10-11 days and 3, 6, and 12 months after therapy. These patients also underwent arginine infusion and L-dopa stimulation tests and had measurements of morning baseline GH-binding protein (GHBP), IGF-I, and IGF-binding protein-3 (IGFBP-3) plasma concentrations. Fourteen sex- and pubertal stage-matched normal volunteers were used as controls. Before therapy, the patient group had an increased body mass index (31.5 +/- 5 kg/m(2)) and markedly decreased plasma mean 24-h GH concentration, mean peak height, and peak area values, with pulse frequency (mean number of peaks) similar to that in the controls. GH Values after arginine and L-dopa stimulation were also subnormal in many of these patients, with 2 of 8 and 8 of 10 failing to show GH responses greater than 7 ng/mL in the respective test. In spite of these findings, plasma concentrations of IGF-I, IGFBP-3, and GHBP were within the normal range in these patients. Surprisingly, a pattern of GH suppression similar to that observed in patients with active disease was also seen in patients who were studied 10-11 days and 3, 6, and 12 months after their cure, when their body mass indexes were progressively normalizing, being relatively stable at 10 days, 26.9 +/- 3.8 kg/m(2) at 3 months, and 24.8 +/- 3.3 kg/m(2) at 12 months. In these patients, plasma IGF-I and GHBP remained normal, whereas IGFBP-3 decreased significantly, albeit within the normal range. The growth rate of 4 patients who were Tanner stage III or below and had not completed their growth at the time of the study increased the year after surgical cure. These findings suggest that patients with Cushing's disease have marked GH suppression during their illness, which, however, does not appear to be a major contributor to the growth suppression observed in this condition. GH hyposecretion continues for at least a year during convalescence, in spite of significant increases in the growth rate in all growing patients. The latter could be explained by the increase in unbound IGF-I levels (normal total plasma IGF-I concentrations with decreased IGFBP-3 plasma levels) in addition to the correction of the glucocorticoid-induced target tissue resistance to IGF-I and other growth factors.