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MINIREVIEW

Growth Hormone Secretion: Molecular and Cellular Mechanisms and In Vivo Approaches

Lloyd L. Anderson^*,,1, Srdija Jeftinija and Colin G. Scanes^*,

^* Department of Animal Science and Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011

¹To whom requests for reprints should be addressed at Department of Animal Science, Iowa State University, 2356 Kildee Hall, Ames, IA 50011–3150. E-mail: llanders{at}iastate.edu

	Abstract

Top Abstract Introduction 1. The Hypothalamic Hormones... 2. Signal Transduction Mechanism... 3. Cellular Mechanism for... 4. In Vivo Approaches... Conclusions References

 
Growth hormone (GH) release is under the direct control of hypothalamic releasing hormones, some being also produced peripherally. The role of these hypothalamic factors has been understood by in vitro studies together with such in vivo approaches as stalk sectioning. Secretion of GH is stimulated by GH-releasing hormone (GHRH) and ghrelin (acting via the GH secretagogue [GHS] receptor [GHSR]), and inhibited by somatostatin (SRIF). Other peptides/proteins influence GH secretion, at least in some species. The cellular mechanism by which the releasing hormones affect GH secretion from the somatotrope requires specific signal transduction systems (cAMP and/or calcium influx and/or mobilization of intracellular calcium) and/ or tyrosine kinase(s) and/or nitric oxide (NO)/cGMP. At the subcellular level, GH release (at least in response to GHS) is accomplished by the following. The GH-containing secretory granules are moved close to the cell surface. There is then transient fusion of the secretory granules with the fusion pores in the multiple secretory pits in the somatotrope cell surface.

Key Words: growth hormone • growth hormones secretagogues • cellular mechanisms • signal transduction systems

	Introduction

Top Abstract Introduction 1. The Hypothalamic Hormones... 2. Signal Transduction Mechanism... 3. Cellular Mechanism for... 4. In Vivo Approaches... Conclusions References

 
A series of stimulatory and inhibitory releasing hormones of hypothalamic and also peripheral origins controls the release of growth hormone (GH) from somatotropes. Until recently, the consensus was of two hypothalamic releasing hormones for GH, respectively GH-releasing hormone (GHRH; stimulatory GH) and somatostatin (SRIF; inhibitory) with GH release and synthesis reflecting a balance between these. In vivo approaches such as stalk sectioning provide strong evidence for the physiological control of GH release (discussed in detail below). There is at least one other hypothalamic releasing hormone for GH with the identification by Kojima and colleagues of ghrelin as the natural ligand for the GH secretagogue (GHS) receptor (GHS-R; Ref. 1). Moreover, in at least some species, GH secretion is influenced by other peptides/proteins produced in the hypothalamus and in the periphery, including gonadotropin releasing hormone (GnRH), insulin-like growth factor 1 (IGF-1), leptin, pituitary adenylate cyclase activating polypeptide (PACAP), and thyrotropin releasing hormone (TRH).

There is increasing knowledge of the subcellular events leading to GH release. This includes signal transduction mechanisms and the physical nature of GH secretory granules fusing transiently with the cell membrane. Recently, our laboratory, in collaboration with Bhanu Jena, established that secretory granules in the somatotrope are moved close to the cell surface and then fused with a specific organelle, the fusion pores being located in the secretory pits in the cell surface (2). The present article reviews GH secretion under the following topics:

1. hypothalamic hormones that influence GH release and synthesis (with particular attention to other peptides as well as GHRH, SRIF, and ghrelin),
   
2. specific signal-transduction systems,
   
3. cell biology for controlled GH secretion involving movement of secretory granules and fusion pores secretory pits of somatotropes,
   
4. in vivo approaches to understanding the physiology of GH secretion.
   

Where possible, examples from studies using domestic animals will be employed.

	1. The Hypothalamic Hormones Controlling GH Release and Synthesis

Top Abstract Introduction 1. The Hypothalamic Hormones... 2. Signal Transduction Mechanism... 3. Cellular Mechanism for... 4. In Vivo Approaches... Conclusions References

 
a. Growth Hormone Releasing Factor (GHRH).
The major function of GHRH, released from neurosecretory terminals in the median eminence, is to stimulate the release and synthesis of GH. GHRH is expressed in the arcuate nucleus of the hypothalamus together with other tissues, for example, intestine, gonads, immune tissues, and the placenta (reviewed in Ref. 3). GHRH immunoreactive (IR) neurons have been identified in coronal and sagittal frozen sections of bovine and porcine hypothalami (4). Rounded bipolar GHRH IR perikarya are localized in ventrolateral regions of the arcuate nucleus (ARC) in both species. GHRH-immunoreactive fibers projected ventrally into the median eminence (ME) in both species.

Signal transduction involves G_s-protein, adenylate cyclase (isoform II and/or IV), cyclic 3', 5'adenosine monophosphate (cAMP), and protein kinase A. There is a cAMP response element (CRE) upstream from the coding region of the GH gene. GHRH increases GH expression (e.g., cattle, Ref. 5; chickens, Refs. 6, 7). Intracellular Ca²⁺ concentrations are increased by GHRH. This involves both influx of Ca²⁺ (via L- and T-type voltage-sensitive Ca²⁺ channels) and by phospholipase C hydrolysis of phosphatidyl inositol, leading to mobilizing intracellular Ca²⁺ stores (reviewed in Ref. 3).

b. Somatostatin (SRIF).
Somatostatin (SRIF) is a cyclic 14- or 28-amino-acid residue containing peptide. A major function of SRIF is suppressing the release, but not synthesis, of GH by the somatotrope (reviewed in Ref. 8). SRIF-IR neurons have been identified in bovine and porcine hypothalamic tissue (4). Bipolar SRIF-IR perikarya are located about the third ventricle in the periventricular nucleus. SRIF-IR fibers project ventrally into the ME. SRIF-IR fibers densely innervate the ventromedial and arcuate (ARC) nuclei in pigs, but are not as distinguishable as in cattle (4). Double immunostaining reveals a close apposition of SRIF-IR fibers with GHRH-IR perikarya in the ARC and ventromedial nuclei and apposition of SRIF- and GHRH-IR varicosities in the ME (4).

The SRIF receptor (sstr) is encoded by five different genes (sstr1–5; reviewed in Ref. 8). The dominant sstr influencing GH release from the somatotrope appears to be sstr-2 (rat; Ref. 9). Signal transduction involves G-protein coupled reduction in L- and T-type voltage-sensitive Ca²⁺ influx/channels and increased K⁺ channels (reviewed in Ref. 8).

c. Ghrelin.
Ghrelin is a natural ligand for the GH-secretagogue receptor (GHS-R; Ref. 10). It is produced by the stomach, small intestine, and central nervous system; for example, the hypothalamus, specifically including the ARC (1, 10, 11). Ghrelin acts by binding to the GHS receptor. The GHS-R is a seven transmembrane domain G-protein coupled receptor (12). Signal transduction involves activation of phospholipase C (via G protein), generation of inositol phosphate and diacyl glycerol, and increased intracellular Ca²⁺ (reviewed in Ref. 13). Ghrelin stimulates GH release both directly, acting at the level of the anterior pituitary gland, and by enhancing GHRH release (for details, see Section 4). The GHS-R is expressed in various hypothalamic and thalamic nuclei, the dentate gyrus, substantial nigra, ventral tegmentum, and facial nuclei of the brainstem, thus implicating a possible central role for ghrelin (14–17). For instance, ghrelin plays a critically important role in the control of appetite, stimulating food intake.

Ghrelin, when injected intracerebroventricular (icv) into rodents, stimulates feeding behavior and an increase in body weight (18, 19). Synthetic GHSs and the endogenous hormone, ghrelin, induce immediate gene c-fos only in the ARC, the site that also contains neuropeptide Y (NPY; Refs. 20–22). Additionally, the ARC and NPY neurons possess GHS-R mRNA, and these neurons also project to orexin-and melanin-concentrating hormone (MCH)—containing neurons in the lateral hypothalamus, neurons that affect feed intake (23, 24). The effects of ghrelin on feed intake appear to be mediated via NPY. Preadministration of the Y1 NPY receptor antagonist (BIB03304) blocks both the stimulatory effects of icv injection of ghrelin or GHRP-6 on food intake in rats, and the decreased body-core temperature (25, 26). Thus, NPY neurons of the ARC are likely a primary site for ghrelin increasing food intake.

It might be speculated that motilin may have analogous effects to ghrelin. Motilin is a highly conserved, 22-aminoacid polypeptide (27) secreted by enterochromaffin cells of the small intestine. This peptide stimulates gastrointestinal motor activity and seems to play a physiological role in the regulation of fasting motility patterns (28). Both IR motilin and mRNA expression are found in the gastrointestinal tract, brain, nerves, and other endocrine glands in several species, including monkey, man, pig, sheep, and rabbit (29). The motilin receptor, designated motilin-R1A (MTL-R1A), is a heterotrimeric, guanosine triphosphate-binding, protein (G protein)-coupled receptor. It was isolated from human stomach, and its amino acid sequence was found to be 52% identical to the human GHSR (30). The high amino-acid-sequence identity between MTL-R1A and the GHSR suggests a role for motilin in the control of GH secretion.

d. Other Hypothalamic Peptides Influencing GH Release Directly.
There are multiple peptides produced by the hypothalamus and periphery that can influence GH release directly. This section will exclude the role of peptides within the hypothalamus and the role of insulin-like growth factors and their binding proteins. The effects of these hypothalamic peptides, some of which are predominantly produced peripherally, may be biologically relevant or pharmacological. However, it is questioned whether the physiological control of GH secretion is much more complex than the two or three releasing hormone model previously envisioned.

i. Thyrotropin-Releasing Hormone (TRH).
The modified tripeptide, TRH, can stimulate the release of GH in many species under some, but not under all, physiological circumstances. For instance, in domestic animals, TRH stimulates GH release in cattle (31, 32), fetal pigs (33), and young chickens (34). Moreover, TRH potentiates the effect of GHRH on GH in young chickens (35, 36) and also postnatal pigs (37). In the case of the latter, the magnitude of the potentiation diminished with age (37). In contrast, administration of TRH had little discernible effect in sheep (fetus or neonates, Ref. 38; lambs, Ref. 39) or postnatal pigs (37) or some fish (turbot, Ref. 40). In contrast, in adult horses, there seems to be an unusual situation with TRH inhibiting provoked GH release. Administration of TRH per se does not influence circulating concentrations of GH in horses (41). However, unexpectedly, TRH reduces the GH secretory response to GHRH (42) and blocks the effects of various physiological stimulators of GH release, including exercise and asparate administration (43). Just as TRH has direct stimulatory effects on GH release in the chicken and augments GHRH-induced GH release acting at the level of the somatotrope in the pituitary gland (see above), analogous inhibitory effects can be envisioned in the horse.

ii. Pituitary Adenylate Cyclase-Activating Peptide (PACAP).
Pituitary adenylate cyclase-activating peptide (PACAP) is a potent GH secretagogue, and has even been proposed as the ancestral releasing factor for GH (reviewed in Ref. 44). In mammals, PACAP 27 and PACAP 38 stimulate GH release in vitro (GH₃ cells, Ref. 45; bovine and porcine somatotropes, Refs. 46, 47) and in vivo (cattle, Ref. 48). In addition, PACAP increases the synthesis of GH as indicated by elevated GH mRNA levels (pig, Ref. 47). In addition, PACAP 27 and 38 have also been demonstrated to stimulate GH release from pituitary cells of birds (chickens, Ref. 49) and fish (50–52).

Based on studies with rat somatotropes, the signal transduction mechanism, via binding to the PACAP type II receptor, for PACAP stimulation of adenyl cyclase/cAMP/ protein kinase A, increases calcium entry via L-type, voltage-sensitive, calcium channels into the cells (44, 53, 54). Pharmacological blockers to phospholipase C-IP3-protein kinase C only partially depress effectiveness of PACAP (55). The signal-transduction mechanism appears to be conserved through vertebrate evolution as PACAP acts via PACAP receptors, cAMP and phospholipase C-IP3-protein kinase C, and voltage-sensitive calcium channels in goldfish (52). There is also evidence for the involvement of tetrodotoxin-sensitive sodium channels in the cellular response to PACAP (56).

iii. Gonadotropin-Releasing Hormone.
In higher vertebrates, gonadotropin-releasing hormone (GnRH) does not stimulate GH release. However, in some species, at specific physiological phases, GnRH can evoke GH secretion. For instance, GnRH stimulates GH release from pituitary cells from neonatal rats (57). In fish, GnRH markedly stimulates GH secretion (e.g., goldfish, Refs. 58, 59; carp, Ref. 60). While GnRH acts via cAMP, there is also evidence that a nitric oxide mechanism may also be involved (61).

iv. Leptin.
The effects of leptin on GH release appear to be predominantly stimulatory. The presence of leptin receptors in/on somatotropes is well established (e.g., Refs. 62–65). There are reports of leptin per se influencing GH release, either stimulating (66, 67) or increasing the responsiveness to GHRH (e.g., Refs. 67–70), or inhibiting (71) or reducing responsiveness to GHRH, for example, in human pituitary adenoma (72). The signal transduction mechanism for leptin appears to be predominantly via JAK II and STAT (reviewed in Ref. 72). In addition, not only does leptin increase nitric oxide (NO) production by pituitary cells, but also an NO donor-stimulated GH release. Inhibitors of nitric oxide synthesis from L-arginine (Ng-monomethyl-L-arginine) inhibited both basal and leptin-induced GH release (73). This would be consistent with leptin acting via NO and NO-sensitive soluble guanylase cyclase.

v. Others (FMRF Amide, Corticotropin-Releasing Hormone, Galanin, and NPY).
Studies, particularly in lower vertebrate species, suggest that somatotropes are promiscuous in terms of the peptides that will stimulate GH release. In some species of lower vertebrates, corticotropin-releasing hormone (CRH) has been reported to stimulate GH secretion (e.g., reptiles, Ref. 74; fish, Ref. 75). Neuropeptide Y has a direct effect of GH release in some species of fish (76, 77). In contrast, galanin can inhibit GH release (78–80). Moreover, peptides related to the neuropeptide Phe-Met-Arg-Phe-NH₂ (FMRF amide), originally described in mollusks, stimulate GH release in amphibians. Similar peptides have been identified in brains of vertebrates (i.e., rat, chicken, frog, carp) with a similar RF amide motif at their C-termini (81–84). A novel hypothalamic RF amide peptide localized in the hypothalamus of the bullfrog has GH-releasing activity and was designated frog GH-releasing peptide (fGRP; Ref. 85).

	2. Signal Transduction Mechanism Systems

Top Abstract Introduction 1. The Hypothalamic Hormones... 2. Signal Transduction Mechanism... 3. Cellular Mechanism for... 4. In Vivo Approaches... Conclusions References

 
a. Adenylate Cyclase/cAMP/Protein Kinase A and Phospholipase C-IP3-Protein Kinase C.
Somato-tropes, excitable cells that exhibit spontaneous action potential, when treated with GHRH, depolarize the cell membrane potential and stimulate Ca²⁺ influx via trans-membrane Ca²⁺ channels, resulting in increases in intracellular free Ca²⁺([Ca²⁺]; Ref. 86). This involves both an influx of Ca²⁺ (via L- and T-type voltage-sensitive Ca²⁺ channels) and phospholipase C hydrolysis of phosphatidyl inositol, leading to mobilizing intracellular Ca²⁺ stores (reviewed in Ref. 3). It is well established that the signal transduction for GHRH, and probably PACAP, involves the following:

1. binding to specific receptors in the plasma membrane of the somatotropes,
   
2. activation of adenylate cyclase (isoform II and/or IV) via the coupling protein, G_s-protein cyclic 3', 5' adenosine monophosphate (cAMP),
   
3. activation of protein kinase A. In addition, there is activation of phospholipase C-IP3-protein kinase C and voltage-sensitive calcium channels.
   

Signal transduction for ghrelin and synthetic analogues or GHS (e.g., GHRP-6 and nonpeptidergic GHS such as L-692, 585, MK-677) involves activation of phospholipase C (via G protein), generation of inositol phosphate and diacyl glycerol, and increased intracellular Ca²⁺ (reviewed in Ref. 13). Modification of the somatotrope’s electrophysiological properties leads to changes in sensitivity to ghrelin or its analogues. The GHRP-6 increases pituitary-specific transcription factor expression in somatotropes, but the mechanism by which ghrelin analogues exert these effects on the pituitary gland is not clear. K⁺ conductance is the predominant membrane ion conductance at resting membrane potential, which regulates cell excitability (87). Long-term (48-hr) treatment with GHRP-2 increased excitability of ovine somatotropes and the levels of voltage-gated K⁺ currents. The increase in the voltage-gated K⁺ currents requires a functional protein kinase C (PKC) system and is achieved through an increase in K⁺ channel protein synthesis (87). Down-regulation of PKC with phorbol 12-myristate 13-acetate at the time of adding GHRP-2 blocked the increase in K⁺ currents. Calphostin C (PKC inhibitor), but not H₈₉ (protein kinase A inhibitor), reduced the increase in K⁺ currents by GHRP-2, whereas inclusion of actinomycin D (transcription inhibitor) or cycloheximide (protein synthesis inhibitor) abolished the increase in K⁺ currents. Thus, GH secretagogues increase the excitability of somatotropes and the voltage-gated K⁺ currents on the membrane. The increase in the synthesis of K⁺ currents is achieved through an increase in synthesis of K⁺ channels, and normal function of the PKC system is required for the increase in voltage-gated K⁺ currents.

We have recently demonstrated, using pharmacological blockers, that both ghrelin and a synthetic GHS can increase intracellular calcium concentrations in porcine somatotrope (88, 89). This two-phase phenomenon involves, first, mobilization of intracellular calcium, followed by calcium entry via L channels with somatotrope depolarization (see Fig. 1; Refs. 88, 89). The effects of GHS are blocked by inhibitors of adenylate cyclase and phospholipase C, supporting the involvement of both these, adenylate cyclase/cAMP/protein kinase A and phospholipase C; in the generation of inositol phosphate and diacyl glycerol and increased intracellular Ca²⁺.

View larger version (17K): [in this window] [in a new window]   Figure 1. Inhibitory effects of ghrelin on calcium transients evoked by L-585 in isolated porcine somatotrophs. (a) Control studies on calcium transients in isolated porcine somatotropes evoked by a 2-min application of human growth hormone releasing-hormone (hGHRH) (10 µM) and L-585 (10 µM; n = 29). (b) Application of L-585 (10 µM) 10 mins after administration of ghrelin (1 µM) did not have an additive effect on [Ca2+]i in isolated porcine somatotropes (n = 58). (c) Ghrelin (100 µM) alone did not affect [Ca2+]i, but the changes in [Ca2+]i evoked by 10 µM L-585 were almost completely blocked (n = 7). (Reprinted from Neuroendocrinology, Vol. 77, Glavaski-Joksimovic A, Jeftinija K, Scanes CG, Anderson LL, Jeftinija S. Stimulatory effect of ghrelin on isolated porcine somatotropes, pp366–378. Copyright 2003, with permission from Karger, Basel.)

	3. Cellular Mechanism for GH Release

Top Abstract Introduction 1. The Hypothalamic Hormones... 2. Signal Transduction Mechanism... 3. Cellular Mechanism for... 4. In Vivo Approaches... Conclusions References

 
Physiological processes, such as neurotransmission, and the secretion of hormones or enzymes, require fusion of membrane-bounded secretory vesicles at the cell plasma membrane and the consequent expulsion of vesicular contents. This final step in the secretory process was little understood. It was believed that, following stimulation of secretion, membrane-bounded secretory vesicles dock and completely incorporate at the cell plasma membrane, to be retrieved by endocytosis later. This would allow the intravesicular contents to be released passively. This common model of exocytosis and endocytosis operating in cellular secretion appeared fine at first; however, severe logistic questions arose. Besides problems of rates and energy requirements for the process, the appearance of empty and partially empty secretory vesicles immediately following secretion were unexplained by the model. Finally, after almost half a century, the molecular mechanism of this vital cellular process has been resolved (2, 93–96).

The molecular mechanism of cellular secretion has recently been resolved by a series of exquisite studies from Bhanu Jena’s laboratory (2, 93–96). These studies reveal, for the first time, the existence of a new cellular structure at the cell plasma membrane, termed porosome. The porosome is a basket-like structure at the cell plasma membrane, having a 100–150 nm diameter opening to the cell exterior (see Fig. 2). Following stimulation of secretion, membrane-bound secretory vesicles dock and transiently fuse at the base of the porosome, expelling vesicular contents. In live cells, stimulation of secretion causes the porosome opening to dilate (20%–35%), returning to resting size following completion of the process (97). Exposure of cells to cytochalasin B, a fungal toxin that inhibits actin polymerization, resulted in a 15%–20% decrease in porosome size, and a consequent 50%–60% loss in stimulated secretion (97). Target SNAREs, or t-SNAREs, present at the base of the porosome interact with vesicle SNARE, or v-SNARE, in a circular array to form a conducting channel, thus establishing continuity between the two compartments (2). Concurrently, following stimulation of secretion, secretory vesicles swell (98, 99), resulting in a buildup of turgor pressure for the expulsion of vesicular contents through the t-/v-SNARE channel and the porosome to the cell exterior. Both the molecular mechanism of vesicle swelling (98, 99) and the molecular structure and partial composition of the porosome (95, 96), have been elucidated (see Figs. 2 and 3). Furthermore, the native porosome has been isolated and functionally reconstituted in liposomes (96).

View larger version (30K): [in this window] [in a new window]   Figure 2. Porosome 1 demonstrates an atomic-force microscopy (AFM) micrograph of the plasma membrane at the apical end of live pancreatic acinar cells, demonstrating the presence of circular pits (yellow arrow) and the 100–150-nm diameter porosomes (blue arrow) within. The right panel is a schematic diagram depicting the porosomes within pits, at the base of which secretory vesicles (ZG) dock and fuse to release vesicular contents. (Courtesy of Bhanu P. Jena.)

View larger version (87K): [in this window] [in a new window]   Figure 3. Transmission electron micrograph of a porosome associated with a docked secretory vesicle at the apical end of a pancreatic acinar cell. (a) Part of the apical end of a pancreatic acinar cell demonstrating, within the green bordered square, the presence of a fusion pore or porosome and an associated zymogen granule (ZG), the electron-dense secretory vesicle of the exocrine pancreas. (Bar = 400 nm.) The area within the green square in (a) has been enlarged to show the apical microvilli (MV) and a section through porosome and the ZG. Note the ZG membrane bilayer is attached directly to the base of the porosome cup. (Courtesy of Bhanu P. Jena.)

View larger version (77K): [in this window] [in a new window]   Figure 4. High-resolution atomic-force microscopy (AFM) performed on resting and stimulated growth hormone (GH)-secreting cells. AFM micrographs of a pit with depressions in resting cell (A), clearly demonstrating the enlargement of depressions or fusion pores following stimulation of secretion (B). Exposure of pits in a stimulated cell (C) to 30-nm gold-tagged GH antibody, results in binding of released growth hormone at the site to 30-nm gold-tagged GH antibody (D). Note the loss of fusion pores due to large amounts of gold-tagged antibody binding at these sites. (Reprinted from Endocrinology, Vol. 143, Cho SJ, Jeftinija K, Glavaski A, Jeftinija S, Jena BP, Anderson LL. Structure and dynamics of the fusion pores in live GH-secreting cells revealed using atomic force microscopy, pp1144–1148. Copyright 2002, with permission from The Endocrine Society, Chevy Chase, MD.)

	4. In Vivo Approaches to Understanding the Physiology of GH Secretion

Top Abstract Introduction 1. The Hypothalamic Hormones... 2. Signal Transduction Mechanism... 3. Cellular Mechanism for... 4. In Vivo Approaches... Conclusions References

 
Among the most powerful techniques used to examine the physiological controls of the anterior pituitary gland is hypophyseal stalk sectioning such that the influences of the hypothalamus are no longer present. There is direct evidence from such studies from pigs and cattle for a balance between stimulatory and inhibitory controls for GH release. This surgery reduces the GH content of the pituitary, but increases responsiveness to GHRH (see Fig. 5, A–C; Refs. 102–106). An interpretation of these observations is that the reduced pituitary GH content reflects depressed GH synthesis due to decreased GHRH stimulation. The increased responsiveness to GHRH results from lack of SRIF inhibition following stalk sectioning. In contrast, the nonpeptidal ghrelin agonist, L-692,585, was much less effective in eliciting GH release in pigs where the hypophyseal stalk had been surgically sectioned (and hence drastically reducing GHRH and SRIF bathing the pituitary; Ref. 107). This is consistent with ghrelin acting directly, either synergistically with GHRH on the somatotropes, or, more likely, exerting its major effect at the level of the hypothalamus by stimulating the release of GHRH and/or inhibiting the release of SRIF. Administration of a ghrelin agonist (the hexapeptide GH-releasing peptide) to sheep has been reported to enhance both GH release and the GHRH concentrations in the portal blood (108).

View larger version (20K): [in this window] [in a new window]   Figure 5A. Growth in beef calves subjected to hypophysectomy (•), hypophyseal stalk transection (), or sham operation () at 146 ± 2 days of age. Birth weight averaged 35 ± 1 kg with subsequent body weights at 21-day intervals. Number of calves is indicated in parentheses. Values are mean ± SE. (Reprinted from Endocrinology, Vol. 140, Anderson LL, Hard DL, Trenkle AH, Cho SJ. Long-term growth after hypophyseal stalk transection and hypophysectomy of beef calves, pp2405–2414. Copyright 1999, with permission from The Endocrine Society, Chevy Chase, MD.) Figure 5B. GH concentration in peripheral serum at 4-day intervals before surgery () and after hypophyseal stalk transection (HST) () and sham-operated control (SOC) (•) of beef calves to day 372 of age. Number of calves is indicated in parentheses. Values are mean ± SE. (Reprinted from Endocrinology, Vol. 140, Anderson LL, Hard DL, Trenkle AH, Cho SJ. Long-term growth after hypophyseal stalk transection and hypophysectomy of beef calves, pp2405–2414. Copyright 1999, with permission from The Endocrine Society, Chevy Chase, MD.) Figure 5C. Growth hormone (GH) concentration in peripheral serum from sequential blood samples at 20-min intervals during 8 hrs in hypophyseal stalk transection () and sham-operated control (•) beef calves. The number denotes the individual calf ear tag identification. (Reprinted from Endocrinology, Vol. 140, Anderson LL, Hard DL, Trenkle AH, Cho SJ. Long-term growth after hypophyseal stalk transection and hypophysectomy of beef calves, pp2405–2414. Copyright 1999, with permission from The Endocrine Society, Chevy Chase, MD.)

View larger version (22K): [in this window] [in a new window]   Figure 7A. Quantitative measurement of plasma prolactin (PRL) and growth hormone (GH) in Meishan pigs at Days 0, 15, and 30. Different letters within the same panel indicate significant differences (P < 0.05). (Reprinted from Animal Reproduction Science, Vol. 69, Sun HS, Anderson LL, Yu TP, Kim KS, Klindt J, Tuggle CK. Neonatal Meishan pigs show POU1F1 genotype effects on plasma GH and PRL concentration, pp223–237. Copyright 2002, with permission from Elsevier, Amsterdam.) Figure 7B. Quantitative measurement of mRNA levels in Meishan pigs for POU1F1-and POU1F1-ß at Days 0, 15, and 30. Letters within the same panel indicate differences of P < 0.05 (a, b) or P < 0.001 (c, d). (Reprinted from Animal Reproduction Science, Vol. 69, Sun HS, Anderson LL, Yu TP, Kim KS, Klindt J, Tuggle CK. Neonatal Meishan pigs show POU1F1 genotype effects on plasma GH and PRL concentration, pp223–237. Copyright 2002, with permission from Elsevier, Amsterdam.) Figure 7C. Statistical analysis identified a significant effect of POU1F1 genotype in Meishan pigs on Day 0 GH and PRL plasma hormone concentrations. Different letters within the same panel indicate significant differences (P < 0.05). (Reprinted from Animal Reproduction Science, Vol. 69, Sun HS, Anderson LL, Yu TP, Kim KS, Klindt J, Tuggle CK. Neonatal Meishan pigs show POU1F1 genotype effects on plasma GH and PRL concentration, pp223–237. Copyright 2002, with permission from Elsevier, Amsterdam.)

View larger version (19K): [in this window] [in a new window]   Figure 6. Growth hormone-releasing factor (GRF) and somatostatin (SRIF) concentration in hypophyseal portal blood and growth hormone (GH) concentration in jugular blood of 2 of 6 conscious, castrated pigs. Each sample represents a 5-min continuous collection. The sampling period was approximately 175 mins for each pig. Significant pulses and SRIF troughs, detected using ULTRA, are indicated by and , respectively. Missing samples are shown as breaks in the splined data points. Values above the y-axis scale are connected by dotted lines. (Reprinted from Proceedings of the Society for Experimental Biology and Medicine, Vol. 217, Drisko JE, Faidley TD, Chang CH, Zhang D, Nicolich S, Hora DF Jr, McNamara L, Rickes E, Abribat T, Smith RG, Hickey GJ. Hypophyseal-portal concentrations of growth hormone-releasing factor and somatostatin in conscious pigs: relationship to production of spontaneous growth hormone pulses, pp188–196. Copyright 1998, with permission from the Society for Experimental Biology and Medicine, Maywood, NJ.)

	Conclusions

Top Abstract Introduction 1. The Hypothalamic Hormones... 2. Signal Transduction Mechanism... 3. Cellular Mechanism for... 4. In Vivo Approaches... Conclusions References

 
While there have been tremendous advances in our understanding of the control of GH secretion, many questions remain. These include the following:

1. Why are there multiple releasing hormones for GH?
   
2. Do all somatotropes respond to all secretagogues?
   
3. Is there a localized signal transduction mechanism(s)?
   
4. Are the receptors for releasing hormones arranged in close proximity to fusion pores?
   

	Footnotes

 
This work was supported by research grant USDA NRI 2003-35206-12817, the Iowa Agriculture and Home Economics Experiment Station, Ames, Iowa, and by Hatch Act and State of Iowa funds.

	References

Top Abstract Introduction 1. The Hypothalamic Hormones... 2. Signal Transduction Mechanism... 3. Cellular Mechanism for... 4. In Vivo Approaches... Conclusions References

 

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