Evaluation of Hypothalamic Dysfunction in Growth Hormone (GH)-Deficient Patients Using Single<i>Versus</i>Multiple Doses of GH-Releasing Hormone (GHRH-44) and Evidence for Diurnal Variation in Somatotroph Responsiveness to GHRH in GH-Deficient Patients*

Schriock, Elizabeth A.; Hulse, J. Anthony; Harris, David A.; Kaplan, Selna L.; Grumbach, Melvin M.

doi:10.1210/jcem-65-6-1177

Cited by 23 publications

(11 citation statements)

References 16 publications

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“…Both baseline and pulse amplitudes were higher at night than during the day in our patients, a phenomenon that clearly cannot be attributed to GHRH. This is in agreement with other, more circumstantial evidence that enhanced nocturnal GH secretion is not fully attributable to GHRH (36,48,62,69) and supports the concept that decreased somatostatin tone contributes to enhanced nocturnal GH secretion (70). In the absence of GHRH action, it is either somatostatin withdrawal, ghrelin pulses, or another, unknown oscillator that must be responsible for residual nocturnal pulse generation.…”

Section: Discussionsupporting

confidence: 91%

Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance

Maheshwari

Pezzoli

Rahim

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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. Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance. Am J Physiol Endocrinol Metab 282: E943-E951, 2002. First published January 8, 2002 10.1152/ajpendo.00537.2001 secretion is regulated by GH-releasing hormone (GHRH), somatostatin, and possibly ghrelin, but uncertainty remains about the relative contributions of these hypophysiotropic factors to GH pulsatility. Patients with genetic GHRH receptor (GHRH-R) deficiency present an opportunity to examine GH secretory dynamics in the selective absence of GHRH input. We studied circadian GH profiles in four young men homozygous for a null mutation in the GHRH-R gene by use of an ultrasensitive GH assay. Residual GH secretion was pulsatile, with normal pulse frequency, but severely reduced amplitude (Ͻ1% normal) and greater than normal process disorder (as assessed by approximate entropy). Nocturnal GH secretion, both basal and pulsatile, was enhanced compared with daytime. We conclude that rhythmic GH secretion persists in an amplitude-miniaturized version in the absence of a GHRH-R signal. The nocturnal enhancement of GH secretion is likely mediated by decreased somatostatin tone. Pulsatility of residual GH secretion may be caused by oscillations in somatostatin and/or ghrelin; it may also reflect intrinsic oscillations in somatotropes.growth hormone-releasing hormone receptor; somatostatin; pituitary gland; short stature GROWTH HORMONE (GH) IS SECRETED in a pulsatile or episodic manner. This secretion pattern is principally governed by hypothalamic growth hormone-releasing hormone (GHRH) and somatostatin (see Ref. 23 for review). Ghrelin (39) and/or a similar endogenous ligand for the GH secretagogue (GHS) receptor may also participate in GH pulse generation, although its role in physiological GH secretion is still largely unknown. GHRH and ghrelin stimulate pituitary GH release, whereas somatostatin inhibits it. In addition to its acute GH-releasing action, GHRH also stimulates GH synthesis (3) and somatotrope proliferation during pituitary ontogeny (41, 68).The pulsatile pattern of GH secretion and its relation to GHRH and somatostatin rhythms has been evaluated extensively in a number of species (23), and a concept of GHRH-induced GH pulses, modulated by prevailing somatostatin tone and rapid somatostatin oscillations, has been formulated (65). A role of ghrelin in this interplay can be postulated but remains unproved. This model is supported by studies using immunoneutralization of GHRH and somatostatin (65, 80), GHRH, or somatostatin antagonists (5,33,34,73), as well as direct pituitary portal sampling in experimental animals (18,20,55,66). A reciprocal relationship between GHRH and somatostatin, where GHRH pulses coincide with somatostatin troughs, has been reported in rats (37,55,65), but this pattern is less clear in sheep or pigs, where more complex relationships between oscillations in GHRH, somatostatin, and GH prevail (8,15,20,66). Thus important species as well as sex differences exist in the regulation...

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Section: Discussionsupporting

confidence: 91%

Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance

Maheshwari

Pezzoli

Rahim

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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“…Studies in the rat (15) and man (7,8) have shown that the response to bolus GHRH stimulation is greatest at times of endogenous GH secretion (when SRIF tone is low and stored GH is available for release), and lowest during the refractory phase between pulses (when SRIF tone is high and stored GH pools are depleted). Knowledge of the pre-stimulatory secretory state is therefore important for interpreting results, and, although many studies have shown a reduced GH response to GHRH stimulation in children with severe idiopathic GH deficiency (16)(17)(18), the variability in this test has limited its usefulness in differentiating children with less marked GH insufficiency from short normal controls (19).…”

Section: Discussionmentioning

confidence: 99%

The GH response to low-dose bolus growth hormone-releasing hormone (GHRH(1-29)NH2) is attenuated in patients with longstanding post-irradiation GH insufficiency

Achermann

Brook

Hindmarsh

2000

European Journal of Endocrinology

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Objective: Previous studies have suggested that post-irradiation GH insufficiency results from a loss of GHRH secretion, since many patients were able to release GH following exogenous GHRH stimulation. However, supramaximal doses of GHRH were used and the response may decline with time after radiotherapy. We re-evaluated the GHRH dose-response curve in patients post cranial irradiation and in controls. Design: Randomized controlled study. Methods: Five adult male long-term survivors of childhood brain tumours (median age 21.8 years (18.4-26.7); 13.7 years (11.4-15.7) post-radiotherapy, >30 Gy) and five matched controls were studied. An intravenous bolus of GHRH(1-29)NH 2 was administered in doses at the lower (0.05 mg/ kg) and upper (0.15 mg/kg) range of the dose-response curves for young males, as well as the standard supramaximal dose (1.0 mg/kg). GH was measured before stimulation, every 2 min for the first hour and every 5 min for the second hour. All studies were conducted in a random fashion. Results: Significantly lower peak and area under the curve (AUC) GH concentrations occurred in the irradiated group using 0.15 mg/kg (median peak Irradiated, 4.5 mU/l vs median Controls, 37.4 mU/l; P<0.01) and 1.0 mg/kg (median peak Irradiated, 4.8 mU/l vs median Controls, 15.2 mU/l; P<0.05) GHRH(1-29)NH 2 . In irradiated subjects there was an incremental rise in GH output with increasing doses of GHRH(1-29)NH 2 (median AUC: 122 mU/l·min vs 179 mU/l·min vs 268 mU/l·min; P=0.007) reflecting altered pituitary sensitivity and reduced responsiveness. Conclusion:The GH response to bolus GHRH(1-29)NH 2 is attenuated in adult long-term survivors of childhood brain tumours. This may reflect direct pituitary damage and/or the loss of the tropic effects of chronic GHRH deficiency.

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“…The possibility to differentiate the hypothalamic from the pituitary form of GH deficiency with the growth-hormone-releasing hormone (GHRH) test has been doubted [1,2,6,7,15,16], but on the basis of studies performed in small and not homogeneous groups of growth-hormone (GH)-deficient children.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Growth-Hormone-Releasing Hormone Test in Short Normal and Growth-Hormone-Deficient Children

et al. 1990

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Growth-hormone-releasing hormone (GHRH) tests were performed once [GHRH(1–29)NH₂, 1 µg/kg] or on 2 consecutive days [GHRH(1–44)NH₂, 1 and 2 µg/kg administered in random order] in 27 children with idiopathic, isolated growth hormone (GH)-deficiency and in 49 short normal children, all clinically prepubertal. No differences in GH release were found between the tests performed on the 1 st and 2nd day or according to GHRH dose or sex, both in GH-deficient and control children. 80% of GH-deficient and 87% of control children responded (GH peak > IO ng/ml) to GHRH(1–29)NH₂, and 65% of GH-deficient and all control children to GHRH(1-44)NH₂· No differences in GH release were found between GH-deficient GHRH responders and control children. 17% of GH-deficient and 10% of control children responded only to one of the two tests performed on 2 consecutive days; the lack of responsiveness was unrelated to GHRH dose and sequence of GHRH administration (1st or 2nd day). The GHRH test does not seem to be a reproducible test for the evaluation of GH release, nor is it useful to differentiate GH-deficient GHRH responders from short normal children.

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Evaluation of Hypothalamic Dysfunction in Growth Hormone (GH)-Deficient Patients Using SingleVersusMultiple Doses of GH-Releasing Hormone (GHRH-44) and Evidence for Diurnal Variation in Somatotroph Responsiveness to GHRH in GH-Deficient Patients*

Cited by 23 publications

References 16 publications

Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance

Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance

The GH response to low-dose bolus growth hormone-releasing hormone (GHRH(1-29)NH2) is attenuated in patients with longstanding post-irradiation GH insufficiency

Evaluation of the Growth-Hormone-Releasing Hormone Test in Short Normal and Growth-Hormone-Deficient Children

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