Reduced disorderliness of growth hormone release in biochemically inactive acromegaly after pituitary surgery

Abstract

The episodicity of 24 h GH release was studied in 18 patients with active acromegaly, 12 patients 7-10 days after pituitary surgery, 14 patients long after operation (3-17 years), and 21 healthy gender-and age-matched control subjects, using a recently introduced scale-and model-independent regularity statistic, approximate entropy (ApEn). Blood samples were taken at 10-min intervals for 24 h, and plasma GH concentrations were measured by immunofluorometric assay (detection limit 11.5 ng/l). For this study we selected operated patients who were biochemically in remission, defined by normal circulating IGF-I and insulin-like growth factor-binding protein-3 (IGFBP-3) concentrations, normal glucose-suppressed plasma GH concentration (<0.38 mg/l), and the normalization of the paradoxical rise of GH to TRH or GnRH. In patients with active acromegaly ApEn was 1.23 Ϯ 0.04, with no overlap with the control subjects (P ¼ 1.2 × 10 ¹16 ), who had an ApEn of 0.40 Ϯ 0.04. ApEn in patients shortly after surgery was 0.71 Ϯ 0.09 (P < 0.001 vs controls), and long after surgery 0.56 Ϯ 0.05 (P < 0.011 vs controls). ApEn values in treated and untreated patients correlated significantly with the plasma concentration of IGF-I (r ¼ 0.531) and IGFBP-3 (r ¼ 0.598), and the log-transformed 24 h GH secretion rate (r ¼ 0.749). Shortly after surgery only one-third of the patients had a normal ApEn value, whereas long after surgery about 70% of the patients had a normal ApEn value. Although ApEn eventually normalized in about 70% of the operated patients, the cause of the persistence of abnormal GH release in the remainder of the subjects is not known, and might reflect permanent hypothalamic-pituitary dysfunction or a very early recurrence of the somatotroph adenoma.

GH deficiency in patients irradiated for acromegaly: significance of GH stimulatory tests in relation to the 24 h GH secretion

“…However, when compared with values reported in normal healthy subjects, ApEn was elevated almost twofold, indicating disorganized GH secretion (5). Elevated ApEn of GH points to increased feed-forward by GHRH or tumoral cells or decreased feedback via somatostatin, GH and IGF-I signaling (35).…”

“…Ideally, the therapy should be directed towards the restoration of physiological GH secretion, which is achieved when responses to dynamic stimuli and 24 h GH production are normalized, including restoration of secretory characteristics such as diurnal rhythm and secretory regularity. At the present time only surgery is capable of fulfilling these goals in a limited number of patients, even by expert surgery (2)(3)(4)(5). Therefore, frequent additional treatment is required, which may be given in the form of pharmacotherapy (e.g.…”

Orderliness of hormone release patterns: a complementary measure to conventional pulsatile and circadian analyses

“…The paper by Van den Berg et al (19) explores the question of persisting disorderliness of GH secretion in surgically treated acromegalic patients (19). This follow-up study, using an independent GH assay and evaluating a separate patient cohort, corroborates the sentinel insights of Hartman et al (12), and establishes that enhanced disorderliness of GH release can persist in some patients after clinical and biochemical cure of acromegaly via trans-sphenoidal surgery.…”

Octreotide represses secretory-burst mass and nonpulsatile secretion but does not restore event frequency or orderly GH secretion in acromegaly

“…Most plausibly, by analogy with other benign endocrine tumors (18,20,44), properties of transformed somatotrope cells may contribute to irregular (less coordinated) patterns of GH release, as observed here. In this regard, surgical removal of the somatotropinoma normalizes GH ApEn in 70% of patients with operable acromegaly (45).…”

“…Investigations of tumoral GH secretion in active acromegaly have revealed increases in pulse-event frequency, basal (nonpulsatile) secretion, irregularity, and (absolute) diurnal rhythmicity (19)(20)(21)44). In patients with noninvasive adenomas, transsphenoidal surgery can normalize each attribute (43,45).…”