Chronic growth hormone (GH) hypersecretion induces reciprocal and reversible changes in mRNA levels from hypothalamic GH-releasing hormone and somatostatin neurons in the rat.

Abstract

Effects of growth hormone (GH) hypersecretion on somatostatin-(SRIH) and GH-releasing hormone (GHRH) were studied by in situ hybridization and receptor autoradiography in rats bearing a GH-secreting tumor. 6 and 18 wk after tumor induction, animals displayed a sharp increase in body weight and GH plasma levels; pituitary GH content was reduced by 47 and 55%, while that of prolactin and thyrotropin was unchanged. At 18 wk, hypothalamic GHRH and SRIH levels had fallen by 84 and 52%, respectively. In parallel, the density of GHRH mRNA per arcuate neuron was reduced by 52 and 50% at 6 and 18 wk, while SRIH mRNA levels increased by 71 and 83% in the periventricular nucleus (with no alteration in the hilus of the dentate gyrus). The numbers of GHRH-and SRIH-synthetizing neurons in the hypothalamus were not altered in GH-hypersecreting rats. Resection of the tumor restored hypothalamic GHRH and SRIH mRNAs to control levels. GH hypersecretion did not modify 1211-SRIH binding sites on GHRH neurons. Thus, chronic GH hypersecretion affects the expression of the genes encoding for GHRH and SRIH. The effect is long lasting, not desensitizable and reversible. (J.

Central Administration of a Growth Hormone (GH) Receptor mRNA Antisense Increases GH Pulsatility and Decreases Hypothalamic Somatostatin Expression in Rats

“…Intravenous (Willoughby et al, 1980;Clark et al, 1988) and intracerebroventricular (Tannenbaum, 1980;Abe et al, 1983) administrations of human GH strongly decrease GH plasma levels, an effect that has been attributed to inhibition of GHRH synthesis (Chomczynski et al, 1988) and release (Clark et al, 1988), increase in SRIH neuronal activity (Rogers et al, 1988;Lanzi and Tannenbaum, 1992), or both (Miki et al, 1989). Sensitivity of both SRIH and GHRH neurons to GH feedback is also suggested by experiments on hypersomatotropinemic rats, because subcutaneous grafts of tumoral GH cells result in increased SRIH mRNA in the periventricular nucleus (PeV) and decreased GHRH mRNA in the arcuate nucleus (ARC) (Bertherat et al, 1993).Mechanisms involved in these GH effects are not completely elucidated as yet. Nevertheless, recent data indicate that the GH receptor gene is expressed in the rat hypothalamus , and GH receptor mRNA-containing cells have been visualized in the PeV and the ARC, the major respective locations of SRIH and GHRH neurons (Burton et al, 1992;Minami et al, 1993;Burton et al, 1995).…”

Abnormalities of hypothalamic-pituitary-adrenal and hypothalamic-somatotrophic axes in Fawn-Hooded rats

“…Although release of SRIF into the median eminence was not measured in FH rats, it is unlikely, on the basis of our present results, that the reported reduced GH response to serotoninergic agonists in FH rats (7,9) could be explained by an enhanced somatostatinergic tone. Reduced mRNA for SRIF in the presence of normal GH and IGF-I concentrations could be the consequence of a defective response of PeN somatostatinergic neurones to GH and IGF-I, or to a reduction in the biological activity of IGF-I, as both hormones exert a positive feedback on PeN somatostatinergic activity (43)(44)(45)(46)(47)(48). The hypothesis of a defective cellular response to GH or IGF-I is compatible with the dramatic reduction of growth that is observed in FH rats.…”

A botulinum toxin–derived targeted secretion inhibitor downregulates the GH/IGF1 axis

“…Since SXN101742 action primarily involves blockade of the exocytic machinery, VAMP cleavage in this case, inhibition of GH synthesis may reflect the existence of an intracellular feedback mechanism in somatotroph cells, linking the failure of GH-containing vesicles to fuse with the plasma membrane to the repression of de novo GH synthesis. Blockade of GH secretion from somatotrophs could also abolish short GH feedback loops known to control GHRH and SRIF hypothalamic production (43)(44)(45), themselves regulating GH synthesis. In any case, this indirect inhibitory action of SXN101742 on GH synthesis could reinforce its therapeutic value compared with current acromegaly treatments.…”