The Journal of pediatric endocrinology最新文献

Growth hormone secretion is mainly regulated by the interplay of GHRH and somatostatin, two specific hypophysiotrophic neurohormones. In addition to GHRH and somatostatin, many neurotransmitters and neuropeptides influence GH secretion mainly by acting at the hypothalamic level. This paper focuses on the stimulatory role of acetylcholine, arginine and galanin as well as on the inhibitory influence of catecholamines which is mediated by the activation of beta-adrenergic receptors. Attention will be given to the age-related changes in the neural control of GH secretion from childhood to old age.

A large number of somatostatin analogs taken from several major families of peptides has been examined for binding to three newly discovered somatostatin receptors (SSTR1, 2 and 3) transfected and expressed in various cell membrane preparations. Extremely potent octapeptide analogs related to and including octreotide (SMS 201-995) were found to bind with high affinity to SSTR2 receptors, which appear to be primarily of a pituitary type, and indeed affinities correlated extremely well with inhibitory potencies for inhibition of GH release from rat pituitary cells. Several new octapeptides were discovered with affinities and in vitro potencies greater than previously reported analogs. Whereas all of the octapeptides had much lower affinity for SSTR1 and SSTR3 receptors, which appear to be primarily present in the CNS, high affinity and highly specific ligands for the latter were found within a series of linear somatostatin analogs. No analogs were found which had high affinity for SSTR1 receptors. These studies confirm the feasibility of designing ligands which are specific for the various somatostatin receptors. These should provide useful tools for delineating the physiological roles of these receptors, specifically labeling certain receptors, and developing therapeutically interesting compounds targeted towards specific physiological events.

The metabolic state influences GH secretion and, in turn, GH secretion influences overall body metabolism. While these are distinct physiological entities, separation of these interrelated phenomena should be considered artificial since the overall result is an organism which retains functional capacity in the setting of a variety of circumstances.

The growth hormone (GH) secretory pattern changes significantly throughout development in both male and female rats, becoming markedly sexually dimorphic after pubertal onset. This observation suggests that pubertal sex steroids play a role in the manifestation of this phenomenon. The neonatal steroid environment has also been shown to be intricately involved in the generation of the final adult GH secretory pattern, but the mechanisms underlying this effect remain unknown. We have addressed the question as to whether the developmental changes in the GH secretory pattern are correlated with changes in the hypothalamic neuropeptides that regulate its release from the anterior pituitary, i.e., somatostatin (SS) and growth hormone-releasing hormone (GHRH). The effects of neonatal testosterone and adult testosterone treatments on these two neuropeptide systems have also been studied. We have found that the synthetic capacity, as reflected in relative messenger RNA (mRNA) levels, of both SS and GHRH neurons changes throughout development in both male and female rats. These mRNA levels are also sexually dimorphic at certain times during maturation and, at least in the adult male, can be modulated by changes in testosterone levels. In support of the hypothesis that sex steroids play a role in the organization of the developing hypothalamus, we have shown that both estradiol and testosterone promote the survival of hypothalamic neurons in vitro. Preliminary in vivo studies indicate that the neonatal sex steroid environment may influence the number of GHRH neurons that are found in the adult brain, as well as their sensitivity to adult steroids.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of the POU domain transcription factor Pit-1 (GHF-1) in differentiation and proliferation of the somatotrophic lineage is well known. In our study of differential splicing of the PIT1 gene we found a new protein, Pit-2, in which 26 amino acids are inserted into the transactivation domain. Pit-2 can activate the growth hormone promoter but has lost the ability to activate the prolactin promoter or PIT1 promoter itself.

The insulin-like growth factor system, which includes the IGFs, IGF-binding proteins and IGF receptors, plays an essential role in normal growth and development, as well as the cellular differentiation of a number of other important systems, including the reproductive and immune systems. IGF action has also been implicated in several pathological conditions, including tissue repair, malnutrition, diabetes and malignancy.

When unlimited supplies of biosynthetic human growth hormone (hGH) became available in the late 1980s, the envisaged potential of its therapeutic applications was enormous in that it was hoped that perhaps most short children would be able to be made taller. However, this seems to have been far too simplistic a view and certainly in those children with various growth disorders treated with pharmacological doses of growth hormone (GH), the potential for increased final height does not appear to be fulfilled, with the exception of girls with Turner's syndrome. Further challenges in the growth field involve the manipulation of pubertal development during concomitant GH therapy.