Alter Growth Hormone Levels Research Articles

GH Dysfunction in Engrailed-2 Knockout Mice, a Model for Autism Spectrum Disorders

Insulin-like growth factor 1 (IGF-1) signaling promotes brain development and plasticity. Altered IGF-1 expression has been associated to autism spectrum disorders (ASD). IGF-1 levels were found increased in the blood and decreased in the cerebrospinal fluid of ASD children. Accordingly, IGF-1 treatment can rescue behavioral deficits in mouse models of ASD, and IGF-1 trials have been proposed for ASD children. IGF-1 is mainly synthesized in the liver, and its synthesis is dependent on growth hormone (GH) produced in the pituitary gland. GH also modulates cognitive functions, and altered levels of GH have been detected in ASD patients. Here, we analyzed the expression of GH, IGF-1, their receptors, and regulatory hormones in the neuroendocrine system of adult male mice lacking the homeobox transcription factor Engrailed-2 (En2−/− mice). En2−/− mice display ASD-like behaviors (social interactions, defective spatial learning, increased seizure susceptibility) accompanied by relevant neuropathological changes (loss of cerebellar and forebrain inhibitory neurons). Recent studies showed that En2 modulates IGF-1 activity during postnatal cerebellar development. We found that GH mRNA expression was markedly deregulated throughout the neuroendocrine axis in En2−/− mice, as compared to wild-type controls. In mutant mice, GH mRNA levels were significantly increased in the pituitary gland, blood, and liver, whereas decreased levels were detected in the hippocampus. These changes were paralleled by decreased levels of GH protein in the hippocampus but not other tissues of En2−/− mice. IGF-1 mRNA was significantly up-regulated in the liver and down-regulated in the En2−/− hippocampus, but no differences were detected in the levels of IGF-1 protein between the two genotypes. Our data strengthen the notion that altered GH levels in the hippocampus may be involved in learning disabilities associated to ASD.

Suppression of hepatic CYP3A1/2 and CYP2C11 by cyclosporine is not mediated by altering growth hormone levels.

Cyclosporine (CsA) suppresses drug metabolism by decreasing cytochrome P450 (P450) enzyme levels in rat liver. Growth hormone (GH) is known to pretranslationally regulate P450 expression. Thus, the suppression of P450 by CsA may involve GH as an intermediate. To address this question, we examined the effects of administering exogenous GH via twice daily subcutaneous injections and in conjunction with chronic subcutaneous CsA administration for 14 days on hepatic P450 expression. CsA alone decreased CYP3A1/2 and CYP2C11 significantly, in a manner similar to that previously found. When administered in the absence of CsA, GH also suppressed CYP3A1/2 and CYP2C11 protein levels as compared with GH vehicle. In the presence of CsA, GH did not cause further suppression of either CYP3A1/2 or CYP2C11 expression when compared with CsA treatment with GH vehicle. Testosterone in vitro catalytic assays confirmed that CsA and GH separately cause significant decreases in activity levels. Also, the concomitant administration of GH and CsA caused lowered production of 16alpha-, 2alpha-, 6beta-, and 2beta-hydroxytestosterone as compared with the administration of GH with CsA vehicle and as compared with the administration of GH vehicle with CsA. This study shows that GH is a dominating factor over CsA in determining hepatic P450 expression and activity. In addition, CsA does not seem to alter GH levels as a mediating event in suppressing P450 expression and activity. Since CsA given in combination with GH further suppressed P450 activity as compared with CsA given in combination with vehicle, this suggests that changes in hormonal status are likely to be one of the many factors that is responsible for the lack of a clear association between cyclosporine dosing and markers of toxicity.

Plasma insulin and growth hormone during antarctic residence.

Circulatory levels of insulin and growth hormone (GH) were estimated in nine tropical euglycemic men in New Delhi and during the first week of every month of stay in Dakshin Gangotri, Antarctica. Prolonged residency in Antarctica did not alter GH levels because mean GH values during Austral summer and Austral winter were not significantly different from the New Delhi values. Compared with GH, the insulin levels during March, April, and June were found to be significantly lower than the New Delhi values. In Antarctica, the insulin levels in March, April, May, June, July, and August were also found to be significantly lower than the December values. This decline in insulin in Antarctica might be important in increasing substrate availability for heat production by facilitating lipolysis and hepatic glucose output.

Corticosteroid‐induced growth hormone secretion in normal and obese subjects

In normal subjects, corticosteroids stimulate growth hormone (GH) secretion at 3 hours. Obesity is associated with blunted GH secretion. In order to clarify both the deranged mechanism of GH secretion in obesity and the corticosteroid mechanism of action we have assessed in normal and obese subjects the effects of dexamethasone, pyridostigmine (a drug capable of suppressing somatostatin release) and GHRH. We also compared in normal subjects the stimulatory effect of three different corticosteroids on plasma GH levels. In both normal and obese subjects the following tests were carried out: placebo; dexamethasone alone (4 mg i.v. at 0 minutes); and dexamethasone plus pyridostigmine (120 mg p.o. at 60 minutes). In normal subjects we also studied the effects of hydrocortisone (100 mg i.v. at 0 minutes) and deflazacort (a corticosteroid that does not cross the blood-brain barrier) (60 mg i.v. at 0 minutes). In obese subjects we also assessed the effect of dexamethasone plus GHRH (100 micrograms i.v. at 150 minutes) on plasma GH levels. Ten normal subjects and 22 obese subjects were studied. Normal controls were within 10% of their ideal body weight. Obese subjects had a body mass index of 37.1 +/- 1.1 (mean +/- SEM). Plasma GH levels were measured by radioimmunoassay. Dexamethasone-induced GH secretion in normal subjects (28.6 +/- 7.8 millimicron/l, P less than 0.05). Corticosteroids did not alter GH levels in obese subjects. Pretreatment with pyridostigmine increased dexamethasone-induced GH release in normal subjects (40.8 +/- 6.8 millimicron/l) but this did not achieve statistical significance. Dexamethasone plus pyridostigmine did not alter GH levels in obese subjects (8.0 +/- 1.6 mU/l). In some subjects, dexamethasone pretreatment potentiated GHRH-stimulated GH secretion, while in half the subjects the basal GH levels were not altered. In control subjects, hydrocortisone and deflazacort caused GH release similar to dexamethasone. Corticosteroids are a new and selective stimulus of GH secretion. They do not cause GH release in obese subjects. Their relative independence from cholinergic control suggest that they act by reducing somatostatin secretion.