Regulation of GH Secretion in Acromegaly: Reproducibility of Daily GH Profiles and Attenuated Negative Feedback by IGF-I

GH hypersecretion is a hallmark of acromegaly. It is unknown whether the secretory activity of somatotroph adenoma is autonomous or is still governed by central or peripheral mechanisms. In this study we investigated whether GH secretion in acromegaly 1) has a reproducible circadian pattern and 2) is inhibited by exogenous IGF-I. Eleven patients with newly diagnosed acromegaly were studied in 2 protocols. In protocol 1, peripheral blood was sampled every 10 min for 48 h in 6 patients for the determination of concordance between 24-h GH profiles. There was no significant day to day variability in mean 24-h output. There was, however, a significant time effect, and the 24-h GH secretion pattern was maintained between days. In protocol 2, 5 patients were sampled for GH every 10 min twice, once during infusion of normal saline and once during iv infusion of recombinant human IGF-I (10 μg/kg·h). The recombinant human IGF-I infusion increased plasma IGF-I to approximately 230% of the baseline concentration. This resulted in GH suppression (4220 ± 1950 vs. 3223 ± 1472 μg/liter·min; P = 0.001), but did not alter GH secretion pattern. There were highly significant cross-correlations for 10 of the 11 of the subjects in the two protocols when the lag was 0 min. By harmonic analysis, nocturnal augmentation of GH was maintained, and maximum daily GH occurred at approximately 2300 h. These data demonstrate that the pattern of GH secretion in acromegaly is not random, but is highly preserved with 24-h periodicity. In addition, negative feedback regulation by IGF-I is preserved, although the degree of negative feedback is grossly attenuated. Thus, secretory activity of somatotroph adenomas is not autonomous or haphazard, but is still subject to both feedback and feedforward regulatory mechanisms.

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Gender-Dependent Role of Endogenous Somatostatin in Regulating Growth Hormone-Axis Function in Mice

Endocrinology ◽

10.1210/en.2007-0946 ◽

2007 ◽

Vol 148 (12) ◽

pp. 5998-6006 ◽

Cited By ~ 30

Author(s):

Raul M. Luque ◽

Rhonda D. Kineman

Keyword(s):

Prolactin Receptor ◽

Feedback Regulation ◽

Receptor Expression ◽

Mrna Levels ◽

Male Mice ◽

Negative Feedback Regulation ◽

Male And Female ◽

Gh Secretion ◽

Igf I

It has been previously reported that male and female somatostatin (SST) knockout mice (Sst−/−) release more GH, compared with Sst+/+ mice, due to enhanced GH-secretory vesicle release. Endogenous SST may also regulate GH secretion by directly inhibiting GHRH-stimulated GH gene expression and/or by modulating hypothalamic GHRH input. To begin to explore these possibilities and to learn more about the gender-dependent role of SST in modulating GH-axis function, hypothalamic, pituitary, and liver components of the GH-axis were compared in male and female Sst+/+ and Sst−/− mice. Pituitary mRNA levels for GH and receptors for GHRH and ghrelin were increased in female Sst−/− mice, compared with Sst+/+ controls, and these changes were reflected by an increase in circulating GH and IGF-I. Elevated levels of IGF-I in female Sst−/− mice were associated with elevated hepatic mRNA levels for IGF-I, as well as for GH and prolactin receptors. Consistent with the role of GH/IGF-I in negative feedback regulation of hypothalamic function, GHRH mRNA levels were reduced in female Sst−/− mice, whereas cortistatin (CST) mRNA levels were unaltered. In contrast to the widespread impact of SST loss on GH-axis function in females, only circulating GH, hypothalamic CST, and hepatic prolactin receptor expression were up-regulated in Sst−/− male mice, compared with Sst+/+ controls. These results confirm and extend the sexually dimorphic role of SST on GH-axis regulation, and suggest that CST, a neuropeptide that acts through SST receptors to inhibit GH secretion, may serve a compensatory role in maintaining GH-axis function in Sst−/− male mice.

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