Kerry L. Hull

Neural growth hormone: an update.

It is now well established that growth hormone (GH) gene expression is not restricted to the pituitary gland and occurs in many extrapituitary tissues, including the central and peripheral nervous systems. Indeed, GH gene expression occurs in the brain prior to its ontogenic appearance in the pituitary gland, and GH may have evolved phylogenetically as a neuropeptide, rather than as an endocrine. Recent studies on the regulation and roles of neural GH in health and disease are the focus of this brief review.

Growth hormone: roles in male reproduction.

Growth hormone (GH), as its name suggests, is obligatory for growth and development. It is, however, also required for sexual differentiation and pubertal maturation and participates in gonadal steroidogenesis and gametogenesis. These roles are likely to reflect the endocrine actions of pituitary GH, directly at gonadal sites and indirectly via hepatic insulin-like growth factor-1. However, because GH is also produced in gonadal tissues, it may act in paracrine or autocrine ways to regulate local processes that are strategically regulated by pituitary GH. The concept that GH is a major regulator of male reproduction is the focus of this review.

GROWTH HORMONE : A PARACRINE GROWTH FACTOR IN EMBRYONIC DEVELOPMENT?

Although pituitary growth hormone is obligatory for normal postnatal growth and development, early embryonic and fetal growth is generally considered to be independent of pituitary GH. Indeed, in chickens, somatotrophs and serum GH are not detectable until late in embryogenesis, and neither partial decapitation nor pre-hatch GH administration greatly affects embryonic growth. However, since it is now known that GH can be produced and act in many extra-pituitary tissues, early embryonic growth may be independent of pituitary GH but dependent upon the paracrine actions of extra-pituitary GH. The possibility that growth hormone may be a paracrine growth factor during early development will therefore be considered in this brief review, which is based on the embryogenesis of the domestic fowl.

Cellular localization of growth hormone receptors/binding proteins in immune tissues

Abstract.It is well established that the activity and proliferation of lymphoid cells and lymphoid organs are stimulated by growth hormone. These actions on lymphoid cells may be direct or mediated by actions on the epithelial and non-immune tissue cells that regulate immune function. The occurrence and cellular localization of growth hormone receptors in immune tissues has therefore been investigated to determine the target-sites of growth hormone action. Growth hormone receptor mRNA was first detected by Northern blotting in the spleen, bursa of Fabricius, and thymus of domestic fowl. In addition to the 4.4-kb transcript thought to encode the full-length growth hormone receptor, smaller transcripts of 2.8 kb and 1.0 kb, which may encode growth hormone-binding proteins, were also occasionally observed. Further analysis using the polymerase chain reaction revealed that mRNA sequences encoding the extracellular and intracellular domains of the growth hormone receptor were present in all tissues and highly homologous with hepatic transcripts. Translation of these transcripts also occurs in immune tissues, since immunoreactive growth hormone-binding proteins or growth hormone receptors of approximately 56 kDa were detected in hepatic, splenic, thymic, and bursal extracts. Immunocytochemistry of these tissues subsequently revealed that macrophages probably contain the bulk of this immunoreactivity, although some thymic medullary epithelial cells (including Hassall’s corpuscles) and splenic ellipsoids and interdigitating cells were also immunoreactive. This immunoreactivity is present in immune tissues of newly hatched and adult chickens. Importantly, B-lymphocytes were rarely, if ever, immunoreactive, and T-lymphocytes containing growth hormone receptors or binding proteins were not observed. These results suggest that a number of primary (thymus and bursa) and secondary (spleen) lymphoid tissues in the chicken contain growth hormone receptors and are thus target-sites for growth hormone action. The distribution of growth hormone receptor/growth hormone-binding protein immunoreactivity in these tissues would further suggest that growth hormone plays a major role in macrophage proliferation and/or activity and may indirectly affect lymphocyte maturation and storage via effects on thymic and splenic stromal cells.

Growth hormone and reproduction: a review of endocrine and autocrine/paracrine interactions.

The somatotropic axis, consisting of growth hormone (GH), hepatic insulin-like growth factor I (IGF-I), and assorted releasing factors, regulates growth and body composition. Axiomatically, since optimal body composition enhances reproductive function, general somatic actions of GH modulate reproductive function. A growing body of evidence supports the hypothesis that GH also modulates reproduction directly, exerting both gonadotropin-dependent and gonadotropin-independent actions in both males and females. Moreover, recent studies indicate GH produced within reproductive tissues differs from pituitary GH in terms of secretion and action. Accordingly, GH is increasingly used as a fertility adjunct in males and females, both humans and nonhumans. This review reconsiders reproductive actions of GH in vertebrates in respect to these new conceptual developments.

Expression of the growth hormone gene in immune tissues.

It is well established that growth hormone (GH)-like proteins and mRNA are present in immune tissues, but it is not known whether this reflects ectopic transcription of the GH gene or the expression of a closely related gene. This possibility was, therefore, investigated. Immunoreactive (IR) GH-like proteins were readily measured by radioimmunoassay and immunoblotting in the spleen, bursa of Fabricius and thymus of immature White Leghorn chickens, in which IR-GH was similar in size and antigenicity to the major GH moieties present in the pituitary gland. RT-PCR of mRNA from these immune tissues, with oligonucleotide primers spanning the coding region of pituitary GH cDNA, also generated cDNA fragments identical in size (689 bp) to pituitary GH cDNA.BamHI andRsaI cleavage sites were located in these cDNA sequences in the same position as those in pituitary GH cDNA. These amplified cDNA sequences also contained sequences that hybridized, by Southern blotting, with a chicken pituitary GH cDNA probe, thus suggesting a high degree of homology between pituitary and immune GH transcripts. The nucleotide sequence of the PCR products generated from these immune tissues, determined by a modified cycle dideoxy chain termination method, were also identical to pituitary GH cDNA. This homology extended over 593 bp of the spleen cDNA (spanning nucleotides 70–663 of the pituitary GH cDNA and its coding region for amino acids 5–201), 613 bp of the bursa cDNA fragment (spanning nucleotides 63–676 of the pituitary GH cDNA and its coding region for amino acids 3–207) and 607 bp of the thymic cDNA fragment (spanning nucleotides 61–665 of pituitary GH cDNA and its coding region for amino acids 4–203). These results clearly establish that the GH mRNA is present in immune tissues, in which GH-IR proteins are present. The local production of GH within the immune system of the domestic fowl, therefore, suggests it has paracrine or autocrine roles in modulating immune function.

CALCITROPIC PEPTIDES : NEURAL PERSPECTIVES

In mammals and higher vertebrates, calcitropic peptides are produced by peripheral endocrine glands: the parathyroid gland (PTH), thyroid or ultimobranchial gland (calcitonin) and the anterior pituitary gland (growth hormone and prolactin). These hormones are, however, also found in the neural tissues of lower vertebrates and invertebrates that lack these endocrine organs, suggesting that neural tissue may be an ancestral site of calcitropic peptide synthesis. Indeed, the demonstration of CNS receptors for these calcitropic peptides and their induction of neurological actions suggest that these hormones arose as neuropeptides. Neural and neuroendocrine roles of some of these calcitropic hormones (calcitonin and parathyroid hormone) and related peptides (calcitonin gene related peptide, stanniocalcin and parathyroid hormone related peptide) are thus the focus of this review.

Neural calcitropic peptides: immunoreactive characterization in fish and invertebrates.

Parathyroid hormone (PTH) and stanniocalcin (STC) are primarily produced by the parathyroid glands and corpuscles of Stannius in tetrapods and fish, respectively. However, it is now known that both calcitropic peptides are also synthesized outside of these specialized endocrine glands. The current study employed Western blot analysis to characterize PTH and STC in neural tissues of high- (rats) and low- (hagfish, dogfish, rockfish, trout and skate) vertebrates and invertebrates (starfish, squid, cuttlefish, snails, prawns). Immunoreactive PTH-like peptides, comparable in size to PTH 1-84, were readily detectable in brains of vertebrates lacking (fish) and possessing (rat) parathyroid glands and in invertebrate (snail) ganglia. Immunoreactive STC-like peptides of varying size were similarly detected in brains of vertebrates lacking (rat) and possessing (fish) corpuscles of Stannius and in invertebrate (snail, prawn) ganglia. STC and PTH may thus have evolved as ancestral neuropeptides.

Avian somatotrophs: differentiation, morphology, distribution, and regulation

Growth hormone (GH) is primarily synthesized, stored, and released by pituitary somatotrophs. These cells comprise a highly labile population that continuously undergoes proliferation, differentiation, and morphogenesis in response to changing physiological stimuli. They are also functionally and morphologically heterogeneous with distinct spatial and temporal distribution within the pituitary gland. The characteristics of these cells are discussed in this brief review.

Growth hormone receptor synthesis and release in tumorous somatolactotrophs

The growth hormone (GH) receptor (GHR) gene is expressed in pituitary somatotrophs and lactotrophs, in which GHR/GH-binding protein (GHBP) immunoreactivity is primarily located in secretory granules. The possibility that the GHR gene may be similarly expressed in GH3 cells was therefore investigated, since these tumorous pituitary cells are used as models of GH- and prolactin-secreting cells but lack secretory granules. GHR/GHBP gene transcripts were detected in GH3 cells and were homologous to hepatic GHR/GHBP transcripts. Immunoreactive GHRs were also detected by Western Blotting and GHBP/GHR immunoreactivity was localized by immunogold electron microscopy within each intracellular compartment. Although the immunoreactive GHR/GHBP content of these cells was less than that in rat tissues, GHBP release from GH3 cells into incubation media (relative to tissue content) was much greater than GHBP release from rat tissue explants. These results demonstrate GHR expression in GH3 cells, comparable with that in normal pituitary cells. These tumorous somatolactotrophs could thus provide a model for studies on GHR/GHBP synthesis and release and for studying GH effects on pituitary function. The release of GHBP from pituitary cells also indicates, for the first time, an extra-hepatic source of the plasma GHBP.