Impaired growth hormone secretion associated with low glucocorticoid levels: an experimental model for the Giustina effect.

Abstract

Hattori et al. [1] in this issue of Endocrine report on an interesting experimental model of dioxin-induced fetal growth retardation. This study found that oral administration of dioxin to pregnant rats reduced both the pituitary expression and serum levels of growth hormone (GH) in perinatal pups [1]. Concomitantly, dioxin decreased serum concentration of corticosterone in the studied model. Administration of physiological doses of corticosterone to dioxin-exposed mothers restored or tended to restore the dioxin-induced reduction of both GH expression and fetal body weight [1]. Taken together, these observations suggest that dioxin-induced fetal growth disorders are due, at least in part, to impaired GH expression and secretion in the presence of low circulating glucocorticoids [1]. GH is secreted in pulses by the pituitary gland. It is regulated by the hypothalamus via the stimulating factor GH-releasing hormone (GHRH) and the inhibitory hormone somatostatin [2]. In addition to classic hypothalamic peptides, many other neuropeptides (ghrelin and galanin), neurotransmitters (acetylcholine), metabolic substances (glucose and amino acids), and circulating hormones (thyroid and sex hormones) modulate GH production [2–6]. Regulation of GH secretion is deranged in many human diseases including Cushing syndrome [7–9]. In fact, glucocorticoids are among the most relevant circulating hormones acting as GH regulators with multiple effects at hypothalamic (increase somatostatin tone), pituitary (expression of GH and GHRH receptor), and peripheral level (decreased production of insulin-like growth factor 1, IGF-I, which is the peripheral mediator of GH action) [10, 11]. Interestingly, findings of Hattori et al. [1] are in agreement with data suggesting that glucocorticoids may be crucial for differentiation and maturation of somatotropes [12, 13]. Glucocorticoids can also enhance the GH response of somatotropes to GHRH and ghrelin as effect of enhanced expression of their receptors on pituitary cells [14–16]. In vivo studies suggest that glucocorticoids may both stimulate and inhibit GH secretion with the net biological effect related to hormonal levels and duration of exposure [10, 11]. In fact, as authors of the Endocrine paper correctly pointed out [1] although maternal co-treatment with corticosterone at low dose (1 mg/kg) restored defects produced by dioxin, higher doses such as 10 mg/kg corticosterone failed to produce beneficial effects on dioxin-exposed fetuses. In the adrenalectomized rat a blunted GH secretion in response to GHRH was observed while glucocorticoid replacement restored GH secretion to normal [17]. The work by Hattori confirmed that glucocorticoids may in vivo, as well as in vitro, directly stimulate GH secretion with a non-hypothalamic action. In fact, in the rats, administration of supraphysiological doses of glucocorticoids resulted in a decreased GH secretion and this effect appeared to be determined by an increase of somatostatin and decrease of GHRH in hypothalamus [18–20]. In vivo, long-term administration of glucocorticoids in the rats resulted in a decrease in body growth and/or weight and a profound catabolic state which was restored by passive immunization with somatostatin antibodies and somatostatin type 2 receptor antagonists [21, 22]. The study by Hattori et al. constitutes an interesting and innovative in vivo model for the evaluation of physiological effects of glucocorticoids on GH secretion which in A. Giustina (&) G. Mazziotti University of Brescia, Poliambulatori di Via Biseo,Via Biseo 17, 25123 Brescia, Italy e-mail: a.giustina@libero.it