Control of growth hormone secretion in the vertebrates: A comparative survey

Camp. Biochem.

0300-9629/86 $3.00 + 0.00 Pergamon Journals Ltd

Physiol. Vol. 84A, No. 2, pp. 231-253, 1986

Printed in Great Britain

REVIEW CONTROL OF GROWTH HORMONE SECRETION IN THE VERTEBRATES: A COMPARATIVE SURVEY T. R. HALL,*? tWolfson

S. HARVEY?

and C. G.

SCANES*$

Institute, University of Hull, Hull, HU6 7RX, UK. Telephone: 0482-497067; SDepartment Animal Sciences, Rutgers-The State University, New Brunswick, NJ 08903, USA

of

(Receiz& 11 October 1985)

INTRODUCTION

noradrenaline, serotonin, garnma-aminoamine, butyric acid, histamine, acetylcholine, etc.) may control GH release by regulating the secretion of these hypothalamic peptides.

The existence of growth hormone (GH, somatotrophin) was first demonstrated in the early 1920s by the ability of pituitary gland extracts to stimulate growth in rats. In the 1960s and 1970s GH was isolated and chemically characterized in a number of different vertebrate species (reviewed by Cocchi and Locatelli, 1983) and its physiology subjected to continuous investigation. In recent years, considerable advances have been made in the techniques available to examine the control of GH secretion, the more noteworthy including the production of specific radioimmunoassays for GH in a variety of species, and the isolation and characterization of the three major hypothalamic hormones involved in the regulation of GH secretion, i.e. thyrotrophin releasing hormone (TRH), GH release-inhibiting hormone (somatostatin, SRIF) and GH-releasing factor (somatocrinin, GRF). These developments have accelerated GH research and are responsible for a rapid expansion in the scientific literature. This recent information is evaluated in the present review, in which comparative mechanisms in the control of GH secretion are discussed.

(3) Feedback Release of GH may be regulated by a short loop feedback mechanism, where GH acts on hypothalamic activity (either releasing hormones or neurotransmitters), or a long loop feedback mechanism, where secretions from target tissues (such as liver somatomedins and thyroid hormones) regulate hypothalamic activity directly or via “higher centres” of the central nervous system (CNS). There is also some evidence for ultrashort loop feedback systems by which releasing factors may regulate their own release. (4) Other hormones and metabolic factors GH dietary

release is modulated by interactions with metabolites and other endocrine glands.

ENVIRONMENT

CONTROL OF GH SECRETION

A generalized scheme for the control of GH secretion in the vertebrates is depicted in Fig. 1. Several sites where GH secretion may be regulated are shown.

3

(1) Basal secretion The pituitary gland may be capable significant amounts of GH in the absence influences. The GH cells may be targets latory influences of other hormones and

I HYPOTHALAMUS a) b)

transmitters b)

peptides

metabolites

ADRENALS

2

of releasing of external for modudrugs.

ANTERIOR - PITUITARY GH

a) steroids b) amines _ -

GONADS steroids

1

(2) Hypothalamus There is considerable evidence that the vertebrate hypothalamus contains several releasing and releaseinhibiting influences (TRH, SRIF, GRF and other peptides). Hypothalamic neurotransmitters (dop-

*Present address: de Recherches Switzerland.

Fig. I. Central and peripheral control of growth hormone secretion: (I) basal secretion; (2) hypothalamic control; (3) feedback; (4) regulation by other hormones and metabolic factors; (5) external factors.

Biovet Unit, CIBA GEIGY SA, Centre Agricoles, CH- 1566 Saint-Aubin FR, 231

c B.P e-%,2*-c

232

T. R. HALL PI al.

Steroids in particular may alter the responsiveness of the pituitary gland and hypothalamus. Amino acids, glucose, fatty acids and various inorganic ions also may profoundly affect GH secretion in several species at hypothalamic or pituitary sites of action. (5) External factors Various stresses, including restraint, temperature fluctuations, anaesthetics and food shortage, have marked effects of GH secretion. Seasonal factors may alter GH secretory patterns in animals living in their natural environment. I.

BASAL SECRETION OF GH

When the pituitary gland is removed from hypothalamic influence, e.g. by excision of the gland and either incubation in vitro or transplantation to a site away from the hypothalamus, release of GH generally falls precipitously and remains at a low level thereafter (Ball, 1981). However, it should be noted that transection of the hypophyseal stalk of ovariectomized pigs fails to reduce mean overall serum GH concentrations (Klindt et a/., 1983). Although transplantation of chicken pituitary glands to the mesenteric artery produces immunohistological evidence of reduced GH cell number, size and granulation (El Tounsey, 1979) nevertheless, in vitro the gland releases immunoassayable GH during at least 3 days of incubation (Chadwick et al., 1981). Autotransplanted pituitary glands of some amphibians stimulate a more rapid growth than usual, which may be due to secretion of GH rather than, or in addition to. secretion of prolactin (a hormone which is also growth-promoting in amphibia). Although circulating GH in bullfrog (Rana catesbeiana), measured with an homologous assay, increases during metamorphic climax, GH antiserum does not prevent metamorphosis (Clemons and Nicoll, 1977) so it is difficult to assess GH secretion based on amphibian growth and development. Following cultures of some teleost pituitary glands in vitro, GH cells are moderately activated (Ball, 1981; Cocchi and Locatelli, 1983). Hence GH cells in certain vertebrate species may possess considerable autonomy of function, or at least not depend upon hypothalamic stimulation to maintain detectable hormonal output. In mammals, the basal release of GH in vitro is dependent upon the presence of Ca’+, and the release process is activated by cyclic adenosine 3’,5’-monophosphate (CAMP) and prostaglandins (PCs) (Gomez-Pan and Rodriguez-Arnao, 1983; Stachura. 1983). Calcium apparently activates the release of GH through a calmodulin-dependent mechanism, as penfluridol, a calmodulin antagonist, decreases the induced release of GH in vitro (Schettini et al., 1983). Basal release of GH from fowl pituitary glands in rirro may not depend upon an external source of Ca* +, but its release is stimulated by CAMP, and in citro responsiveness to provocative stimuli is dependent upon the Ca* + concentration of the incubation medium (Scanes and Gross, 1983). In contrast, Hall et al. (1986b) have shown that, though GH release from pituitary glands incubated in Ca’ +-free medium is relatively high, nevertheless, GH release increases with increasing Cal+ concen-

trations in the medium. This discrepancy may be due to the fact that Hall et al. (1986b) preincubated glands with a Ca*+ chelator (EGTA) to reduce intracellular sources of Ca*+. Chickens fed on a Ca* + -deficient diet show reduced plasma GH concentrations for up to several weeks on this diet (Sommerville et al., 1983; Harvey et al., 1984~). The role of PGs in control of GH release is not clear. err vivo, PGs reduce GH secretion in young birds and reduce responsiveness to secretagogues, but are without effect in vitro (Harvey, 1983a). However, their effects on stimulated release in vitro have not been investigated. The Ca* +, CAMP and PG requirements for GH secretion from pituitary glands of other vertebrate species have not been determined. As with many other pituitary gland hormones. the basal plasma concentration of GH in domestic animals has a regular pattern of peaks and troughs representing episodic secretion. In the domestic fowl, episodic GH secretion has a relatively fast frequency (approx 1 hr) and an amplitude that diminishes approximately 20-fold with age (Harvey, 1983a; Scants ef al., 1983a). In contrast, in farm ruminants there arc less-frequent GH secretory episodes of a smaller amplitude (e.g. Driver and Forbes, 1981). The rat also shows characteristic episodic bursts of GH secrction that apparently involve both stimulatory and inhibitory signals from the hypothalamus, and specific hypothalamic lesions suppress these spontaneous pulses (Willoughby et al., 1983). Similarly in the pig, pituitary stalk transection abolishes episodic release of GH (Klindt et al.. 1983). The perifused pituitary gland does not show episodic GH release (Stachura, 1983). Episodic GH pulses have also been reported in dogs (Cowan et al., 1984), humans (Webb et a/., 1984), rabbits (Chihara et a/., 1983) and many other species, and the frequency and amplitude of these bursts of GH release appear to be highly species-dependent. It is possible that hypothalamusmediated, pulsatile secretion of GH is a common feature in the vertebrates, though this remains to bc determined. 2. HYPOTHALAMIC

CONTROL OF GH SECRETION

Secretion of GH from the vertebrate pituitary gland is controlled by way of hypothalamic releasing and release-inhibiting peptides whose secretion, in turn, is apparently regulated by hypothalamic monoamines and other central neurotransmitters (Ball, 198 1; Arimura and Culler, 1985). In addition, the possibility arises that the transmitters may have direct effects on the GH cells (see Fig. 2a). The method of transport of the hypophysiotrophic substances varies in the different vertebrate groups, in conjunction with the diverse anatomical configurations of the hypothalamo-hypophyseal complex in the different species, as summarized diagrammatically in Fig. 2b-d. Generally, in tetrapods the active substances (peptides and amines) arise in the hypothalamus, are released into portal vessels within the median eminence, and are then transported to the anterior pituitary cells. In teleosts, neural tissue interdigitatcs with anterior pituitary tissue and the hormone secreting cells may be directly innervated by peptide- and amine-containing neurones. In “primitive” verte-

Control

233

of GH in vertebrates

(a) Hypothalamo - pituitary SysteIII

(b) Teleostr ,

RPD

(c) Amphibia

AP kl) Birds -

Fig. 2. Anatomy of hypothalamepituitary complex in the vertebrates. Key: Am N, aminergic neurone; Ca, caudal zone of adenohypophysis; Ce, cephalic zone of adenohypophysis; I, intermediate zone; ME, median eminence; N, neural lobe of neurohypophysis; NI, neurointermediate zone; OC, optic chiasma: PeN. peptidergic neurone; PPD, proximal pars distalis; PR, pars tuberalis of adenohypophysis; PV, portal vessels; RPD, rostra1 pars distalis; SV, saccus vasculosus; VIII, third ventricle.

brates, some species may possess rudimentary portal vessels, whereas others may depend upon simple diffusion of the hypothalamic secretions to the pituitary tissue (see Ball, 1981, for review). However, it should be noted that somatostatin fibres, as well as transmitter-containing neurones, have been localized immunohistochemically in the rat anterior pituitary gland in close proximity to GH-secreting cells, though these fibres are fewer in number than those found in the median eminence (Westlund et al., 1983). This suggests that at least some pituitary cell activity may be regulated through direct neural innervation. Whether this is a vestigial situation or represents an alternate regulatory system has yet to be determined. Both the releasing (GRF) and release-inhibiting (SRIF) hormones have been isolated from mammalian hypothalami, but their detection in other vertebrate species by immunological techniques (see Ball, 1981) or by bioassay (e.g. Hall and Chadwick, 1979) suggests that similar, if not identical, peptides exist in most vertebrate groups. In addition, TRH also has GH-releasing actions under certain circumstances, and other hypothalamic peptides undoubtedly play a role in the regulation of GH secretion. The amount of GH secreted into the general circulation depends not only upon the relative amounts of the peptide factors present, but also upon the sensitivity of the somatotrophs to each releasing/inhibiting hormone, which may be modified by prior exposure of the cells to the hormones (i.e. potentiation or refractoriness) or by other factors

(principally other hormones) present in the systemic circulation. Further support for hypothalamic regulatory system controlling GH secretion, in addition to pituitary incubation bioassay and immunochemical identification of mammalian-like peptides, comes from brain (particularly hypothalamus) electrolytic lesion and stimulation experiments (for birds. see Harvey, 1983a; Rabii et al., 1984). Specific hypothalamic areas (but nevertheless containing a fair degree of overlap) appear to contain GH-stimulatory as well as GH-inhibitory sites which are in agreement with immunohistochemical mapping of somatostatin sites in the young domestic cockerel (Rabii et al., 1984). (I) Thyrotrophin releasing hormone (TRH) Mammalian TRH is a modified tripeptide (pyro Glu-His-ProNH,) which stimulates the release of GH in addition to thyrotrophin. In mammals, GH responses to TRH are not universal, though this may be a consequence of steroid alteration of pituitary responsiveness (e.g. see Sonntag et al., 1982) or even time of day of injection (Caroff et al., 1984). In humans, GH responses are seen best in some pathological conditions such as acromegaly and hypothyroidism, where hypothalamic inhibitory influences may be disrupted. Several in vitro models support this contention. Thyrotrophin releasing hormone is a much more effective GH releasor when pituitary glands from hypothyroid rats are tested in vitro (Szabo et al., 1984) and, in addition, if the acro-

234

T. R.

HALL ef al.

megalic condition is mimicked by preexposing rat anterior pituitary cells to GRF, the GH cells become responsive to the stimulatory influence of TRH (gorges CCal., 1983). In addition, it has been shown that TRH stimulates rat GH secretion prenatally and neonatally, when the pituitary gland is relatively insensitive to SRTF inhibition (Khorram et al., 1983. The tripeptide has more marked GH-stimulating actions in infant rats when catecholaminergic inputs are removed by pretreatment with 6-hydroxydopamine. Apparently, mammalian pituitary glands do not become refractory to TRH stimulation, since daily treatment for up to 90 days does not diminish GH responses to TRH (Sonntag et al., 1978). The rat pituitary tumour clonal cell line, GH,C,, also releases GH in response to TRH (Aizawa and Hinkle, 1985). Thyrotrophin releasing hormone has been located in the hypothalami of other vertebrate species, suggesting a possible n~uroendocrine role (Ball, 1981). The synthetic peptide is a potent stimulator of GH release in birds, including pigeons, chickens, ducks, turkeys and geese, both in vitro and in vivo (Harvey, 1983a; Proudman, 1984). The tripeptide is effective in chickens embryonically at the time of hatch (“pipping”) (Decuypere and Scanes, 1983), evokes a massive release of GH in young birds, but is without

effect in conscious adult birds (Harvey, 1983a). However, TRH stimulates GH secretion in adult birds following pentobarbitone anaesthesia, which probably removes thyroid or SRF suppression (Harvey, 1983b; Harvey ef al., 1983, 1984b, 1985; Harvey and Scanes, 1984). After TRH, the chicken pituitary gland becomes temporarily refractory to a second TRH challenge in L&O, but later responses may be potentiated. This refractoriness is secretagoguespecific, since TRW-refractory birds respond to hpGRF, and vice versa (Harvey and Scanes, 1985; Scanes and Harvey, 1985). Leung et ul. (1984a) have shown that daily administration of TRH to chicks stimulates GH secretion and somatic growth. Their results also clearly demonstrate (though they report otherwise) a reduced responsiveness to TRH by the fifth day of its administration. Although the mechanisms of refractoriness and potentiation are not known, several possibilities are suggested (e.g. see Harvey et al., 198.5; Scanes and Harvey, 1985). Refractoriness may be due to enhanced SRIF release, unlikely since heterologous stimuli are adequate or even supranormal, “down regulation” of pituitary receptors or to ultrashort loop feedback at the pituitary gland level. The mechanism of potentiation may involve alterations in trans-membrane potential due to decreased permeability to K+. These possible mechanisms have not been experimentally investigated. Thyrotrophin releasing hormone is enzymatically degraded to form either the deamidated free acid pyro Glu-His-Pro (TRH-OH) or is cleaved and subsequently modified to His-Prodiketopiperazine (DKP). It is possible that these products may be biologically active in their own right (Grifliths er al., 1982). However, the effects of these peptides on GH release in mammals have not been reported. In birds, both peptides have small GH stimulating activities, but less than 1% of that of TRH itself, and both peptides synergise with TRH in stimulating GH

secretion. Interestingly, the serum enzyme(s) responsible for inactivating TRH shows an age-related increase, suggesting that the reduced response to TRH in conscious adult fowl may be due to a more rapid degradation of TRH (Scanes et crl., 1985). In vitro DKP may antagonize TRH actions on GH release from fowl pituitary glands (unpublished observations). The stimulation of GH release by TRH in vitro is a Ca’+ -dependent phenomenon (Aizawa and Hinkle, 1985). In the fowl, responsiveness to TRH increases with increasing CaZ + concentrations from 0 to ISmM Ca2+, and thereafter decreases until no stimulation is seen in medium containing 6 mM Ca” (Ha11 et al., 1986b). However, chicks reared on a low Ca2+ diet show normal in vivo responses to TRH stimulation (Harvey et al., 1984c), so the precise role of Ca* + in pituitary responsiveness is still unclear. Although the administration of exogenous TRH increases GH release in the domestic fowl. this does not necessarily imply that endogenous TRH is involved in the control of GH release. However, administration of an antiserum which neutralizes endogenous stores of TRH reduces basal plasma concentrations of GH (Klandorf et uf., 1985) suggesting that the peptide does maintain normal GH levels. The physiological situations where TRH may participate in the regulation of GH secretion in birds therefore requires further investigation. Recent data from our laboratory (Hall and Chadwick, 1983b, 1984a) show that TRH also stimulates release of GH from the pituitary glands of other vertebrate species incubated in vitro, including reptiles (chelonian spp), amphibia (anuran spp) and a teleost (European eel, Anguillu utzguiliu). Howcvcr, Wigham and Batten (1984) and Batten and Wigham (1984) failed to find any consistent effects of TRH on GH secretion from molly (Pbecilia lati#~r~u) pituitary glands in vitro. Since TRW generally is less effective, or even without effect on thyrotrophin secretion in poikilothermic vertebrates (Ball, 1981; Hall and Chadwick, 1984a), it is possible that TRH may have evolved primarily as a GH (and prolactin) release-promoting peptide. To confirm this hypothesis, the number of species examined must be greatly extended and responses in many cases confirmed ir? t&o. (2) Somatostatifl (SRfF) The tetradecapeptide SRIF 3 (Ala-Gly-CysLysAsn-Phe-Phe-Trp-Lys-Thr$:he-Thr-Ser-CysOH). as well as a N-terminally extended form SRIF,,, have been detected in both mammalian and nonmammalian hypothalam~ (Ball, 1981; Harvey, 1983a). Although identical peptides have been isolated from species as diverse as the anglerfish, pigeon and rat, other GH release-inhibiting peptides with lesser homology with SRIF,, have also been isolated from teleost tissues (reviewed by Gomez-Pan and Rodriguez-Arnao, 1983). Other SRlFs have also been found in mammalian ‘and avian tissues. In addition to SRIF,, and SRIF,,, porcine duodenum contains two N-terminally extended forms of the smaller peptide with 20 and 25 amino acids, rcspectively. These different peptides. whose biological roles are not all firmly established, appear to be

Control of GH in vertebrates cleavage products from a common prosomatostatin precursor containing I I6 amino acid residues (Arakawa and Tachibana, 1984). The preprosomatostatin sequence also yields SRIF-28,_,,, and which have not, however, been PreproSRIF,,,,, tested for physiological activity (Benoit et al., 1984). Hasegawa et al. (1984) have isolated four SRIF-like peptides from chicken hypothalamic extracts, one identical (except for one amino acid substitution) to SRIF?,, one identical to SRIF,,, a further SRIF,, h ith different chromatographic properties from the mammalian peptide, and a I6 amino acid peptide mith low biological activity. It is well established that SRIF is a GH releasing-inhibiting peptide in vitro and in viuo in mammals, and is able to reduce GH secretion evoked by a wide variety of provocative stimuli (Sonntag et al., 1982; Gomez-Pan and Rodriguez-Amao, 1983; Arimura and Culler, 1985). To circumvent rapid metabolic degradation of SRIF, many modified analogues have been produced, such as substitution of L-amino acids for the D-form (e.g. Redekopp et al., 1984). A cyclic hexapeptide (cycle Pro-Phe-DTrp Lys-Thr-Phe) shows biological properties of SRIF mith extended duration of action in vivo. A highly modified analogue (cycle NMeAla-Tyr-DTrp Lys-Val-Phe) is 56100 times more potent than SRIF,, in inhibiting GH release (Veber et al., 1984). An octapeptide analogue, presumably resistant to enzymatic degradation, has a long-lasting suppressive effect on GH secretion in human acromegalics (Plewe er al., 1984). Generally, there is very good agreement between estimates of biological potency of SRIF analogues and their binding affinities (Schonbrunn et ul., 1983). Injection of an SRIF antagonist analogue increases plasma GH in rats, suggesting a role for endogenous SRIF in the maintenance of basal GH levels (Fries et a/., 1982) and, in lambs, autoimmunization against SRIF increases plasma GH and somatic growth rates (Spencer et al., 1983). Interestingly, an antagonist analogue (cycle Ahep-Phe-D-TrpLys-Thr(BZ1) stimulates growth in weanling female rats, suggesting a possible role of SRIF in regulating growth (Spencer and Hallett, 1985). Other evidence indicating that SRIF may play a physiological role in the maintenance of GH secretory patterns in mammals comes from responses to passive SRIF immunization. Treatment with SRIF antiserum rapidly, though temporarily, increases plasma GH in both young and old rats and in young baboons. Since the GH response to SRIF antiserum increases with age, the involvement of SRIF in the control of GH release may be developmentally acquired. In support of this, it has been shown that SRIF antiserum does not affect GH levels in the foetus or newborn but increases GH levels in rats only from 2 days after birth, indicating that the postnatal decline in GH secretion is due to functional activation of SRIF neurones (Oliver et al., 1982). Episodic release of GH may be due to withdrawal of SRIF inhibition (Cowan et al., 1984), though this is disputed by the findings of Katakami et al. (1984). Perifusion of dispersed rat somatotrophs with bursts of SRIF produces suppression of GH release in the presence of SRIF, with overshoot of GH during the

235

absence of SRIF in the medium, a response evocative of the GH secretory bursts seen in uivo (Cowan et al., 1983). The rebound phenomenon cannot be accounted for solely on the basis of release of material stored during the inhibitory phase of the perifusion (Rene et al., 1982; Cowan et al., 1984). Redekopp et al. (1984) have speculated on the mechanism of GH rebound on termination of SRIF or SRIF analogue infusion in vivo. They suggest that SRIF may inhibit GH release more than synthesis, leading to a build-up of releasable GH in the pituitary gland, or that low concentrations or metabolic products of SRIF, both conditions produced at the end of the infusion, may stimulate GH secretion, though to date there is no convincing evidence to support any hypothesis. Somatostatin acts at the pituitary gland level to reduce activity of adenylate cyclase, both in rat and human pituitary adenoma cells, via a GTP-dependent mechanism (Spada et al., 1984). However, pretreatment of mouse pituitary tumour cells with SRIF, a treatment which primarily reduces adenylate cyclase activity in response to provocative stimuli, produces a desensitization of adenylate cyclase to the inhibitory action of a subsequent SRIF challenge, while increasing enzyme responsiveness to stimulatory influences (Reisine and Takahashi, 1984). It is suspected that SRIF,, is not merely a precursor of SRIF,,, but has distinct physiological functions of its own, though these functions are not clearly defined at present. However, the larger peptide has been shown to behave differently from SRIF,, with respect to binding to SRIF receptors, has different potencies from SRIF,, in certain in vitro and in viuo tests as well as having longer-lasting actions in suppressing hormone release, and is located in separate and distinct neuronal systems. In addition, cysteamine stimulates release in vitro and depletes hypothalamic stores in vivo of SRIF,, without affecting SRIF,, levels (Tannenbaum et al., 1982; Iwanaga et al., 1983; Millar et al., 1983; Bakhit et al., 1984). Rat hypothalamic translation products contain only a single somatostatin precursor (preprosomatostatin), which presumably is differentially processed in the SRIF,, and SRIF,, neurones (Ivell and Richter, 1983, 1984). In several avian species SRIF,, and SRIF,, inhibit GH secretion in vitro and in viuo, though the peptides are much more effective when GH secretion is stimulated, e.g. by GRF or TRH administration (Harvey, 1983a; Leung and Taylor, 1983). The two GHinhibiting peptides are detectable in peripheral and portal plasma, and their degradation appears to involve different mechanisms (Di Scala-Guenot et al., 1984). In ducklings, SRIF infusion reduces plasma GH levels, and after the infusion is discontinued there is a prompt rebound to levels above control, an effect not seen in adult ducks, suggesting that adults have a more developed SRIF control control system which can react rapidly to changing plasma GH concentrations (Harvey, 1983a; Strosser et al., 1984, 1985). The SRIF system is present embryonically in birds (BlPhser, 1983) but is probably only functionally active from about 4 to 6 weeks of age, when plasma GH levels fall (Harvey, 1983a). In poikilothermic vertebrates, the effects of SRIF have received little attention. Hall and Chadwick

T. R.

236

HALL et af.

(1984a) have shown that SRIF,, inhibits TRH- and hypothalamic extract-stimulated release of GH from several chelonian reptile and anuran amphibian pituitary glands in L&o. Cod (Gadus g&s) hypothalami apparently contain a GH release-inhibiting activity (Hall and Chadwick, 1979). Synthetic SRIF inhibits GH release From tilapia (.Surotiwoden mnssamhicus) pituitary glands in r&o (see Ball. 1981), reduces plasma GH levels in the goldfish (Carassius awatuS) as measured by homologous (carp) GH radioimmunoassay (Cook et af., 1983; Cook and Peter, 1984) and inhibits synthesis and release of GH from Porcilia latippinu pituitary glands incubated in citro (Wigham and Batten, 1984; Batten and Wigham, 1984). Since SRIF-like immunoactivity has been detected throughout the vertebrates and even in “ancestral” vertebrates such as the tunicates (Ball, 19S1), it is possible that this peptide may have a GHregulating role in all vertebrate species. (3) Growth

Aormone

releasing fbctors

(GfW)

(i) Identity and actions in mamr~als. Although it has long been recognized that mammalian hypothalami contain GH-releasing activity. isolation studies using large pools of hypothalamic tissue were generally unsuccessful. The breakthrough in GRF characterization came with the isolation of several GHstimulating peptidcs from pancreatic tumours of acromcgalic patients in the laboratories of Guillemin and Vale (reviewed by Gomez-Pan and RodriguezArnao, 1983; Guillemin e’f al., 1984; Frohman, 1984; Arimura and Culler, 1985). Three peptides, designated hpGRF, 44, hpGRF, 40 and hpGRF, ,,, were isolated and their primary sequences determined (that of hpGRF, J4 is Tyr-Ala-Asp-Ala-Ile-PheThr-Asn--Ser-Tyr-Arg-Lys-Val-Leu-Gly-GlnLeu-Ser-AIa-Arg-Lys~Leu~Leu-Gln-Asp-IleMet --Scr-Arg-Gin-Gln~Gly-Glu-Ser-Asn-GlnGlu-.Arg-Gly-Ala-Arg-Ala~Arg-LeuNH~). Subsequently another peptide, hpGRF, 2’J,was described. The shorter peptides. all with common NH, terminal residues, may be degradation products of the parent hpGRF, 44 molecule, or they may possess separate physiological identities and functions, a fact yet to be determined. Two precursors to hpGRF, prepro GRF-107 and prepro GRF-108, have been isolated by molecular cloning techniques, and the mRNA sequences both contain the hpGRF, 44 sequence flanked by initiating signal and termination signal codons (Gubler et al., 1983). Human hypothalamic GRF,., is identical to hpGRF, 35. whereas bovine (bGRF, 94) and ovine (oGRF, +,f hypothalamic GRFs show several amino acid substitutions. Caprine GRF and bGRF have identical sequences, differing in one position from oGRF (Brazeau et al., 1984). Rat hypothalamic GRF, 4J shows only about 67% homology with hpGRF (Biihler et al., 1984). An ectopic GRF has also been partially purified from liver metastatic tumour tissue of an acromegalic patient. The sequenced GRFs show striking homology with the secretin-glucagon family of gastrointestinal peptides, which includes VIP, GIP, gastrin, motilin and the recently-discovered peptide, PHI (Guillemin et al., 1984; Frohman, 1984). The GH-releasing peptides all stimulate GH re-

lease from a wide variety of mammalian pituitary preparations in vitro, including tumour cells from human and murine donors (except the rat GH, clonal cell line), effects reversed by SRIF (Guillemin et al., 1984; Frohman, 1984; Lance et ul., 1984). Long-term incubation of rat pituitary cells with hpGRF, Jo stimulates synthesis. as well as release, of GH but does not appear to affect responsiveness to further stimulation (Dieguez et al., 1984). However, in rats bearing autotranspIanted pituitary glands, hpGRF pretreatment, but not that of TRH, potentiates the GH response to an hpGRF challenge (Janssen er CI!.. 1985). Itl L+COpretreatment of rats with hpGRF, :
of GH in vertebrates

Control

volvement of the peptide in regulation of GH secretion in the embryo (Ohnura et al., 1984). In young men, GH secretion is higher, and responses to hpGRF greater, than in old men (Shibasaki et a/., 1984). Similarly in rats in vim, but not in vitro, the responsiveness to hpGRF declines with age (Sonntag et al., 1983) suggesting an increased secretion of, or increased sensitivity to, SRIF in older animals. However, it should be noted that Wehrenberg and Ling (1983b) failed to find any age-related differences in responses to hpGRF between young and old rats, though they did report an age-related decline in non-stimulated GH secretion. (ii) Mechanisms of action. The proposed mechanisms of action of GRF on GH release are summarized in Fig. 3. A number of intracellular events are postulated to occur from activation of membrane receptors before GH is finally released. ( I) The first event to occur is that specific receptors on the cell membrane bind GRF (Seifert et al., 1985). Analogues of hpGRF with position-l substitutions show differences in binding ability and biological potency, and receptor-ligand interactions apparently require hydrogen bond formation with an aromatic residue at position-l (Ling et al., 1984a). Morel et al. (I 984) have provided immunocytochemical evidence for localization of GRF at the plasma membrane of somatotroph cells. Glucocorticoids may induce GRF receptors (Seifert et al., 1985). (2) Binding of the ligand to the receptor then leads to activation of adenylate cyclase (Labrie et al., 19X3). Spada et al. (1984) have shown that adenylate cyclase activation is positively encouraged in the presence of GTP. Cannico et al. (1983) have demonstrated an increase in membrane phosphatidylinositol formation (as measured by ‘*P’+ incorporation) following GRF activation of receptors. It is possible

NUCLEUS

INT

CELLULAR

237

that GRF receptor activation produces molecular events within the membrane similar to those described by Hirata and Axelrod (1980) namely a production of alkylated phospholipids that result in an increased membrane fluidity and hence increase the likelihood of receptor-adenylate cyclase interaction, as well as possibly revealing Ca*+ channels through the membrane. Metabolism of newly-formed phospholipids, a mechanism to reduce fluidity, may also release the PG precursor arachidonic acid. A phospholipase A? inhibitor and a hpoxygenase inhibitor both reduce GRF-induced GH secretion, suggesting that phospholipid metabolism may be an integral component of GRF actions on GH release (Cronin et al., 1985). (3) Intracellular CAMP concentrations increase in a Ca’+ -dependent fashion, following treatment with hpGRF, 44r hpGRF, J0, hpGRF, ,,, analogues of hpGRF, ectopic (liver tumour-derived) purified GRF and natural human hypothalamic GRF, and responses to submaximal GRF concentrations are potentiated in the presence of 8-bromo-CAMP. forskolin and choleratoxin (which activate adenylate cyclase) and isobutylmethylxanthine (a phosphodiesterase inhibitor) (Brazeau et al., 1982; Bilezikjian and Vale, 1983; Webb et al., 1983; Arimura et al., 1984; Cronin et al., 1984; Frohman, 1984; Guillemin et al., 1984). Since cycloheximide, the protein synthesis inhibitor, potentiates the CAMP response to GRF (Cronin et al., 1984) this suggests that a rapidly turning over protein, possibly phosphodiesterase or an inhibitory unit such as the Ca* + -dependent phosphodiesterase activator, tonically suppresses receptor-activated adenylate cyclase responses. (4) The responses evoked by GRF are reduced by the simultaneous presence of SRIF or somatomedin C, and are enhanced by glucocorticoids and thyroid

CELL

SPACE

MEMBRANE

EXTRACELLULAR

SPACE

other phosphorylation reactions??

receptor interactions

transcription

translation

/ -/

MECHANISMS

OF

ACTION

OF

GRF

Fig. 3. Mechanisms of action of GRF. Abbreviations: AC, adenylate cyclase; protein kinase; SC, somatomedin c. Other abbreviations and numbers

Glu, glucocorticoids; explained in text.

Pk,

238

T. R. HALL etu(.

hormones (Frohman, 1984). In birds, at least, TRH may also increase hpGRF responsiveness (Leung and Taylor, 1983; Harvey et al., i985b), though the mechanism is not known. Spada et al. (1984) have shown that adenylate cyclase activity is dually regulated by hpGRF and SRIF through a GTPdependent mechanism, with CAMP transducing signals of both peptides in GH-secreting cells. Thyroxine, T, and glucocorticoids (including dexamethasone) enhance pituitary responsiveness to GRF acting through adenylate cyciase (Bilezikjian and Vale, 1983; Michel et al., 1983, 1984; Vale et al., 1983; Webb et al., 1983; Wehrenberg et al., 1983; Oosterom et al.. 1984). (5) Peptide-induced release of pituitary gland hormones generally involves a PG-mediated mechanism (Tixier-Vidal and Gourgji, 1981). However, in the case of GRF activation of GH release, the effects of GRF and PGEz are additive, even with maximaliystimulating concentrations of GRF in vitro (Brazeau et al., 1982) though PGE?, like GRF, increases intracellular CAMP production (Michel et al., 1983). These findings suggest that GRF and PGE, stimulate GH release via separate activation of adenyiate cyclase systems. Whether PGE, acts via extracellular receptors coupled to adenyiate cyciase, or whether it acts on various intracellular mechanisms to enhance CAMP fo~ation, is not known at present. (6) The activation of GH release by GRF requires the presence of Ca’+, either from an extracellular source or through the mobilization of bound intracellular Ca’+ . Verapamil, the Ca: + channel blocker, prevents the actions of hpGRF on GH release, but not on CAMP production, suggesting that GH release evoked by hpGRF requires both an increase in CAMP and increased availability of intracellular Ca” (Biiezikjian and Vale, 1983). However, caimodulin antagonists inhibit both adenylate cyciase activity and GH release stimulated by hpGRF (Schettini et ui., 1984). Cobalt chloride, which antagonizes the entry of Ca’+ into ceils, also reduces GRFactivated GH release (Brazeau et al., 1982). (7) Growth hormone releasing factors stimulate GH synthesis as well as release (Dieguez et al., 1984). Human pancreatic GRF,, also stimulates production of mRNA, specifically coding for GH in rat pituitary ceils in primary culture (Glick er af., 1984), but does not affect GHmRNA levels nor GH release in the rat cional GH, ceil line (Zeytin et al., 1984). The exact site of action and the intracellular mediator of the response has not been described, though it is likely that CAMP-activated protein kinase is acting to regulate transcription of the GH gene within the nucleus. (8) Although it is generally accepted that peptide hormones exert their actions an interaction with receptors located on the outer surface of the cell membrane. Morel et al. (1984) have offered immunocytochemicai evidence for an intracellular iocalization of hpGRF in the monkey pituitary gland. Though some hpGRF could be localized on the outer surface of the cell membrane, GRF was also demonstrated on the secretory granules of the somatotrophs and within the nucleus. It is possible that GRF can be taken into the ceil following binding to its membrane receptor, though this does not explain the close

association of immunoreactive material with secretory granules. The physiological significance of these observations remains to be elucidated, though the secretory mechanism may require this translocation of GRF to the granules (Lewin et al., 1983a). (9) Following activation of CAMP production. cahnodulin, and possibly also prostaglandin synthesis by GRF, GH secretory granules arc translocated to the plasma membrane, where their contents are discharged by an exocytotic process into the extracellular space. The secretory granules contain a CAMP-dependent protein kinase that can be directly activated by hpGRF, which increases the affinity of the enzyme towards its substrate CAMP. The protein kinase then phosphorylates specific proteins associated with the secretory granules (Lewin et al., 1983a,b). Presumably exocytoses is initiated by way of this phosphoryiation reaction, (iii) Efsects of GRF i~ other l,ertebrate~. Human pancreatic GRF is an effective stimulator of GH release in birds, both in aifro and in vim. The peptide produces an increase in plasma concentrations of GH in both young and adult chickens, unlike TRH which is effective only in young birds, and it stimulates GH release from chicken pituitary glands in z+tro. These effects are reversed by SRIF (Leung and Taylor, 1983; Harvey and Scanes, 1984, 1985; Harvey et crl., 1984b.c 1985; Scanes and Harvey, 1984,1985; Scanes et al., 1984). Both hpGRF and rat hypothalamic GRF stimulate GH release in turkeys (Proudman. 1984; Huybrechts et a/., 1984). The response is seen in chickens following anaesthesia or in thyroiddeficient dwarf chicks, but is attenuated in normal, conscious fowl (Harvey and Scanes, 1984, 198.5; Harvey et nl., 1984b. 1985; Scanes and Harvey, 1985). Administration of hpGRF causes temporary refractoriness to further stimulation by hpGRF but not to a TRH challenge, suggesting that the two peptides work through separate mechanisms and also showing that refractoriness is not due to depletion of readiiyreleasable GH (Harvey et al., 1985; Scanes and Harvey, 1985). Following maximal stimulation by hpGRF in vitro, further GH release is obtained in the presence of TRH, again emphasizing the fact that the peptides act through separate mechanisms (Leung and Taylor, 1983). Human pancreatic GRF produces release of GH that is not reduced in magnitude in chicks fed on a low Ca’+ diet, suggesting that the reduced basal levels of GH in these birds may bc due, primarily, to a deficiency at the hypothalamic level (Harvey et al., 1984~). Human pancreatic GRF may be much less potent than TRW in stimulating chicken GH release (Harvey and Scanes, 1984), though not apparently in the turkey (Proudman, 1984). This may be a consequence of a difference in primary sequence between hpGRF and the presumptive endogenous chicken GRF. Although a hypothalamic fraction with pronounced GH-releasing activity has been separated from the avian hypothalamus (Hail and Chadwick, 1983a), to date no characterization of avian GRFs has been performed. Even less is known of GRFs in other vertebrate groups. GH releasing activities have been detected and described in crude hypothalamic extracts (Hall and Chadwick, 1979, 1984a; Bail, 1981). Using antiserum directed against hpGRF, 4o and

Control

of GH in vertebrates

GRF, 44. Pan et al. (1985) have localized several distinct neuronal GRF systems in cod hypothalamus and pituitary, and these authors also chromatographically isolated molecular variants of hpGRF which had biological activity in a rat pituitary test in vitro.

(4) Otlw

prptides

A number of pcptides isolated from, or detected immunologically in the mammalian hypothalamus are suspected of possessing a neuroendocrine role (Sonntag et al.. 1982). The failure of antiserum to hpGRF to suppress completely anti-SRIF-induced GH secretion also suggests the presence of other GRFs (Thomas et al., 1985). Vasoactive intestinal polypeptide (VIP), cholecystokinin octapeptide (CCK-R), substance P, bombesin, angiotensin II and motilin may stimulate GH release by actions directly on the pituitary gland cells (Sonntag et al., 1982; Steele c’t d., 1982; Bicknell and Chapman, 1983; Samson et cd., 1984; McCann et al., 1984), though CCK and bombesin also apparently inhibit GH release via hypothalamic actions (Kovastima et al., 1984). VIP stimulation of GH in vitro is reversed by SRIF addition to the medium (Dorflinger and Schonbrunn 1983a,b). VIP may stimulate GH secretion in r>iro in humans (Chihara et al., 1984b). VIP also potentiates the effects of hpGRF in vitro and i?z vivo (Arimura et al., 1984). The peptide PHI,, (porcine intestinal peptide containing histidine and isoleucine, Polak and Bloom, 1984) may also potentiate hpGRF actions in Ctro, though without effect alone (Vigh and Schally, 1984). Secretin and gastic inhibitory polypeptide reduce basal and hpGRF stimulated GH secretion in z%:o in rats (Murphy el al., 1983). Ncurotensin. VIP, bombesin and glucagon also apparently modulate the release of SRIF from the hypothalamus (Abe et al., 1981; Shimatsu et al., 1982). Glucagon administration into the mediobasal hypothalamus tonically reduces plasma GH, an effect reversed by anti-SRIF antiserum, and increases SRIF output (Katakami et al., 1983, 1984). However, in humans, glucagon stimulates secretion of GH, and it may act through a cholinergic muscarinic mechanism (Selitala et al., 1982). Gastrin-releasing peptide, when injected into the ventricles, reverses the stimulatory actions of hpGRF, a response again markedly attenuated by anti-SRIF antiserum, but has no effects on hpGRF-stimulated GH release from the pituitary gland incubated in citro (Kabayama et al., 1984). The 71 amino acid peptide corticotrophin releasing factor (CRF) also has GH releasing-inhibiting activity. Intraventricular injections of CRF into rats reduces spontaneous GH release, without affecting GH release from pituitary cells in vitro (On0 et al., 1984; Rivier et al., l984), and stimulates SRIF secretion from brain cells cultured in vitro (Pieters et al., 1984). It is interesting to note that gonadotrophin releasing hormone may also stimulate GH secretion in men (Amsterdam et al., 1982). Calcitonin inhibits GH secretion in normal fasting human volunteers, possibly through actions in stimulating glucose mobilization (Zofkova et al., 1984). An analogue of eel calcitonin completely prevents spontaneous GH pulses in conscious rats, blocks the PGE-induced secretion of GH in rizw, but has no effects on basal

239

or stimulated GH release from the pituitary gland in vitro (Minamitani et al., 1985). Other peptides have also been isolated from the hypothalamus that may possess GRF-like actions (Arimura et al., 1984). A number of GH-releasing peptides have been designed, synthesized and tested for their GHthe hexapeptide including activity, releasing His-DTrp-Ala-Trp-DPhe-LysNH,. The peptides, though effective in stimulating release of GH, are considerably less potent in their GH-releasing activity from rat pituitary cells than hpGRF, 44r and apparently act through different mechanisms than the native peptide (Badger el al., 1984, Momary et ul.. 1984). Morphine-like peptides, especially methionineenkephalin and /?-endorphin, increase GH secretion, apparently through a hypothalamic neurotransmitter-mediated mechanism. Dermorphin, a synthetic heptapeptide with powerful opiate-like activity, that was originally extracted from skins of South American frogs, also stimulates GH release through a naloxone-sensitive mechanism (Uberti et al., 1983). Since the opiate-antagonist naloxone by itself depresses GH levels, endorphins may play a physiological role in the regulation of GH secretion (Sonntag et al., 1982). Naloxone also blocks suckling and exercise-induced GH release, opiates increase noradrenaline turnover in the hypothalamus, alphaadrenergic antagonists block opiate-stimulated GH release, and administration of an anti-GRF antiserum blocks the enkephalin, morphineand endorphin-stimulated release of GH in vivo (Miki et al., 1984; Murakami et al., 1985; Wehrenberg et al., 1985), suggesting that endogenous opiate compounds stimulate release of GH through an alpha-adrenergicGRF system. Several opioid receptors have been differentiated, based on their ability to bind specific antagonists, though their relative roles in mediating GH responses have not been clearly defined (Delitala et al., 1983a; Koenig et al., 1984). Very little is known of the effects of these peptides on the release of GH in non-mammalian vertebrates. In the young cockerel, in vivo and in vitro, a variety of enkephalin analogues were without effect on GH secretion (Harvey et al., 1978), though their effects on pituitary responsiveness to other secretagogues were not examined. Dynorphin has been found to stimulate GH release in a pituitary-hypothalamus co-incubation system (unpublished observation). Bombesin, given intracerebroventricularly, increased plasma GH levels in anaesthetized chicks (control, 2.03 + 0.43 ng ml, N = 12; bombesin-treated 3.84 f 0.29, N = 12, P < 0.05; unpublished observation). Vasoactive intestinal polypeptide appears to be without effect on GH levels in birds in vivo but stimulates GH from pituitaries of young cockerels in vitro (unpublished). The effects of these peptides on GH release in other vertebrate species have not been examined. (5) Neurotransmitters There is considerable evidence for the involvement of a number of neurotransmitters, especially catecholamines (dopamine, noradrenaline and adrenaline), serotonin, acetylcholine, histamine and gammaaminobutyric acid (GABA), in the regulation of

240

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HALL et al.

activity of hypothalamic peptidergic neurones in mammals (for reviews see Martin-Du Pan and Gomez, 1981; McCann, 1981; Sonntag et ul., 1982; Arimura and Culler, 1985) and birds (for reviews see Scanes et al., 1982, 1984; Harvey, 1983a) and some indications that similar processes also occur in other vertebrates (reviewed by Ball, 1981; Cocchi and Locatelli, 1983). Much of the information is contradictory because of a number of factors, including species differences in responsiveness and lack of specificity of many of the pharmacological agents used in this research. The effects of these neurotransmitters, specifically on GRF or SRIF release, has not been ascertained in the majority of cases. (i) Catecholamines. Sonntag et al. (1981, 1982) have examined the effects of dopaminergic and adrenergic drugs on GH secretion in rats. Dopamine and its agonist piribedil promote the release of GH, effects reversed by the antagonist haloperidol. Clonidine, the alpha-adrenergic agonist, also increases plasma GH, especially in rats treated with alpha-methyl-~” tyrosinc (AMPT) to deplete endogenous catecholamine stores. Pulsatile bursts of GH secretion are at least partly mediated through alpha-adrenergic receptors. since AMPT and the alpha antagonist phenoxybenzamine block these episodic pulses. However, in their review, Sonntag et al. (1982) also report that noradrenaline promotes the release of SRIF from hypothalamic tissue, though Drouva et al. (1982) cite evidence both for stimulation and inhibition of SRIF release by noradrenaline. Kakucska and Makara (1983) showed that following anterolateral hypothalamic deafferentation to remove SRIF innervation while leaving GRF systems intact, dopamine and noradrenaline still stimulate GH release, indicating that at least part of their actions are exerted through GRF. In rats treated with anti-SRIF antiserum. the alpha agonist clonidine, but not the dopamine agonist apomorphine, is able to increase plasma GH, indicating noradrenergic stimulation of GH via GRF activation (Eden et af., 1981). This was confirmed by Miki et al. (1984), who showed that neutralization of endogenous GRF stores with antiGRF antiserum blocks the clonidine-induced secretion of GH in unanaesthetized rats. Differentiation between alpha-l and alpha-2 sub-populations of noradrenergic receptors can be made, since methoxamine (alpha-l agonist) suppresses GH release in dogs, a response blocked by prazosin (alpha- I antagonist), and methoxamine also reverses the stimulatory actions of the alpha-2 agonist clonidine, whereas alpha2 receptor stimulation increases GH release (Cella et cd., 1984a,b). Beta adrenergic receptors may also regulate GH release. Chihara et al. (1984a) suggested that alpha-inhibitory (presumably alpha-l) mechanisms suppress GRF release while stimulating release of somatostatin, whereas beta-receptor mechanisms encourage GH release by inhibiting that of somatostatin. A separate role for central adrenaline is indicated by the observation that adrenaline synthesis inhibitors suppress episodic GH secretion in female rats (Crowley et al., 1982). Catecholaminergic drugs may also affect GH secretion via as yet undefined peripheral mechanisms (including alterations in blood flow and metabolic clearance). The amines themselves (i.e. dopamine, noradrenaline and

adrenaline) probably do not cross the blood-brain barrier. yet adrenaline can prevent secretagogueinduced stimulation of GH release in sheep (Hertelendy ef al., 1972). There appears to be an adrenergic-endorphinergic coupled system for stimulation of GH release, possibly acting through beta receptors (Bluet-Pajot et al.. 1982) though, in addition, naloxonc apparently attenuates responses to clonidine in certain human patients (Branwert and Hokfelt, 1984). In the domestic fowl, AMPT, diethyldithiocarbamate (which blocks conversion of dopamine to noradrenaline), the dopamine antagonist pimozide. the alpha-adrenergic antagonist phenoxybenzamine and the monoamine storage depletor reserpine all reduce plasma GH concentrations, suggesting catecholaminergic stimulation of GH secretion (Scanes et al., 1982). In a subsequent study Buonomo et al. (1984a) showed that administration of large amounts of alpha-l drugs such as phenylephrine or stimulation of noradre~dline avaiIability by treatn~ent with L-dihydroxyphenylserine increase plasma GH when birds are pretreated with AMPT or carbidopa to remove dopaminergic influences. However, injections of very high doses of tricyclic antidepressants (imipramine and desmethylimipramine), which are thought to act by blocking presynaptic reuptake of transmitters and hence increasing postsynaptic availability, also reduce plasma GH concentrations. Apomorphine reduces plasma GH but pimozide appears to be without effect. Buonomo et al. (1984a) concluded that dopamine is probably inhibitory, and noradrenaline (acting through an alpha-l receptor) probably stimulatory in the hypothalamic regulation of GH secretion in the domestic fowl. Using an in citro pituitary--hypothalamic co-incubation system, Hall et al. (1984~) found that dopamine and apomorphine reduce GH release, a response blocked by pimozide, whereas alpha and beta adrenergic drugs appear to be without effect. In addition, dopamine does not affect TRH-stimulated GH release, showing that its effects are mediated through the hypothalamus, though it is not known if the response involves SRIF, GRF or both peptides. Interestingly, the episodic release of GH in fowl is suppressed following treatment with dopamine-beta-hydroxylase inhibitors, phenoxybenzamine and clonidine, suggesting an alpha adrenergic mediation of this phenomenon (Buonomo et at., 1984b). Peripherallyacting adrenergic drugs, as well as adrenaline and noradrenaline, depress plasma GH concentrations in chickens (Harvey, 1983a; Buonomo et ul., 1984a). possibly as a consequence of altered blood flow through the pituitary gland or changes in metabolic clearance of GH. The effects of catecholamines on GH secretion in other vertebrates have received scant attention. Dopamine does not affect basal, TRH- or hypothalamic extract-induced GH release from reptile or amphibian pituitary glands in aitro (Hall and Chadwick. 1984a), though this does not preclude any actions of this amine at the hypothalamic level. By contrast, dopamine may inhibit GH release directly from the pituitary gland of the molly Poecilia lcrtipinna (Ball, 1981). Chang PI a/. (1985) have examined GH responses to catecholaminergic drugs in goldfish,

Control of GH in vertebrates reporting that dopamine may act centratly to stimulate GH release, whereas noradrcnaline may inhibit GH release directly from the pituitary gland, as well as stimulating GH release centrally via an a-receptor-mediated mechanism. (ii) Serotonin. Both serotonin (5hydroxytryptamine) and its precursors 5-hydroxytryptophan and tryptophan increase GH secretion when administered to rats, effects reversed by the antagonists cyproheptidine, methysergide and melatonin (McCann, 1982; Sonntag et al., 1982). The serotonin depleter, ~-chIorophenylalanine @CPA) and the neurotoxin 5,6”dihydroxy-tryptamine reduce, whereas the presynaptic reuptake blocker fluoxetine increases, plasma GH concentrations in mammals (Marti-Henneberg et al., 1980; Sonntag et al., 1982). The pulsatile release of GH in male rats is reduced by pCPA or the antagonist methysergide. However, in dogs, serotoninergic drugs reduce insulin-induced, but not basal, GH secretion (Sonntag et al., 1982). The effects of serotonin on GH-regulating neuropeptides requires elaboration and clarification. Apparently, serotonin does not affect SRIF release, whereas the amine may inhibit reIease of TRH (Drouva ef al., 1982). However, serotonin may reverse cholinergic stimulation of SRIF release from hypothalamic cells cultured in vitro (Peterfreund and Vale, 1983). It is well established that serotonin inhibits the secretion of GH in birds, probably exerting its effects by stimulating the secretion of somatostatin. In vitro serotonin inhibits GH release in both pigeon (Hall, 1982) and chicken (Hall et al., 1984a) pituitaryhypothalamic co-incubations, and pituitary responsiveness and hypothalamic GH releasing activity in z&-o are reduced following in viva administration of serotoninergic drugs to fowl (Hall et al., 1983b). Drugs that enhance serotoninergic activity, including precursors (tryptophan and 5-hydroxy-tryptophan), reuptake inhibitor (imipramine), inhibitors of serotonin degradation (pargyline, clorgyline) and the receptor agonist quipazine, all reduce plasma GH, whereas the synthesis inhibitor p-chlorophenylalanine @CPA) and methysergide and cyproheptidine (receptor antagonists) either prevent these actions or indeed increase plasma GH in fowl (Rabii et al., 1981; Scanes et al., 1982; Hall et al., 1983a, 1984b). There is an inverse relationship between hypothalamic serotonin concentrations and plasma GH levels (Hall et al., 1984b). In addition, feeding chicks a tryptophan deficient diet causes increased plasma GH (Carew et al., 1983). Almost nothing is known of the effects of serotonin on GH secretion in poikilothermic vertebrates. Urueiia and Hall (1986) have shown that administration of tryptophan or the monoamine oxidase inhibitor pargyline increase brain serotonin and pituitary GH concentrations, whereas pCPA reduces serotonin and GH levels in adult grassfrogs (Rana pipiens). The authors suggest that this reflects an increased synthesis, rather than reduced release, of GH. The role of serotonin in regulation of GH in the vertebrates remains relatively uninvestigated. (iii) Acetykholine. The cholinergic agonists pilocarpine and physostigmine, as well as acetylcholine,

241

increase GH release in rats i~z~izw. effects blocked by the antagonist atropine, which by itself has no effects on plasma GH levels (Bruni and Mcitcs. 1978). However, the cholinergic antagonist pirenzipine reverses GH secretion induced by catecholaminergic drugs in humans (Delitala et ul.. 1983b). Tntcrestingly, both pimozide and phentolaminc partly reverse the cholinergic stimulation. suggesting catccholaminergic mediation of the cholinergic responses (Bruni and Meites, 1978). The stimulation of GH by cholinergic drugs appears to involve inhibitton of SRIF release (Richardson et a/., 1980). though contrasting data have been published by Pctcrfrcut~d and Vale (1983). Bicknell and Chapman (1983) rcportcd that acetylcholine stimulates GH rclcasc directly from cultured dispersed bovine pituitary cells, though the response is small and seen only at relatively high acetylcholine concentrations. We have found no effects of cholinergic drugs on release of GH from rat hemi-pituitary glands incubated in ritro (Hall and Bruni, unpublished, quoted in Bruni and Mcites. 1978).

In the domestic fowl, acetylcholine and pilocarpinc inhibit the release of GH in ritro, but only in the presence of hypothalamic tissue, and the rcsponsc is blocked by atropine. GH release in the presence of hypothalamic tissue and acetylcholine is Icsq than that from pituitary tissue alone, suggesting cnhanccment of SRIF release (Hall et al., 1984a). The cholinergic agonist carbachol inhibits GH secretion in the fowl in vivo (Harvey, 1983a). The effects of acetylcholine on cholinergic drugs on GH rclcase in other vertebrate species have not been reported. (iv) Histamine. Histamine is apparcnlly a ccntraf nervous neurotransmitter in mammals and birds. When given intravenously to mammals. histamine sometimes increases GH levels, but this is probably a consequence of a “stress response” (Martin-Du Pan and Gomez, 1981). Sonntag et a(. (1982) also rcported little evidence for histaminergic medialion of GH secretion. Recently, Knigge et nl. (1984) showed that intravenous preinfusion of histamine into normal humans induces a GH response to TRH, which is not normally seen. Conversely, intracerebroventricular administration of histamine in rats reduces episodic GH bursts and also reduces the SRIF antiserum-induced increase in GH secretion, suggesting that histamine reduces GRF release (Netti et al., 1984). Using a pituitary gland-hypothalamus coincubation system we have shown (Hall cr a/., 1984d) that histamine can stimulate the release of GH in the domestic fowl, a response blocked by the H, histamine receptor antagonist diphenhydraminc. In addition an H, agonist given to young cockcrcls intravenously increases plasma GH conccnt~ ;ttions (unpublished observations). Much more rcscarch is required before a definitive role for histaIy?i~~c m regulation of avian GH secretion can be assigned. There are no known reports on the effects of histamine on GH secretion in other vertebrate species. (v) Gamma-aminobutyric acid (GABA). The inhibitory synaptic transmitter GABA is found in high concentrations in the mammalian hypothalamus (Racagni et al., 1982). The effects of (; \I%\ on ?H secretion so far reported ure conirac?i~ I/I 1. 11: !\ II!>

T. R.

242

HALL et al.

stimulatory and inhibitory responses seen (Fick et al., I98 I ; Elias et al., 1982; McCann et al., 1982; Racagni et ul., 1982; Sonntag et al., 1982). The GABA antagonists picrotoxin and bicuculline prevent the rise in plasma GH induced by an analogue of methionine-enkephalin, suggesting a link between opiate and GABA neuronal systems (Katakanii et af., I98 I). Chohnergic st~muiation of SRIF release from fetal rat hypothalamic cells in vitro is prevented by GABA, supporting a GH-stimulatory role for this neurotransmitter (Peterfreund and Vale, 1983). Growth hormone secretion from neonatal rat pituitary glands is also stimulated by GABA in uitro (Acs et al., 1984). In the domestic fowl in vitro, GABA inhibits GH release in the presence of hypothalamic tissue, a response attenuated by both picrotoxin and bicuculline, but none of these drugs affect GH release directly from the pituitary gland (Hall et al., 1984d). Any effect of GABA in other vertebrate species on release of GH is not known. (vi) ~ro~~a~~~~~~~~(PCs). The probable role of PGs is in the secretory mechanism, to control the liberation of both adenohypophyseal and hypothalamic hormones, and possibly also to modulate responsiveness of these tissues to stimulatory and inhibitory substances. Recently, the effects of compounds related to the PGs have been tested in mammalian systems, Various metabolic products of arachidonic acid (the precursor of the PGs) stimulate release of SRIF from rat hypothalamus in vitro and, since these products are formed in hypothalamic

tissue, they may act as regulators of GH secretion (Capdevila et al., 1983). A little-studied PG, prostacyclin (PGI,) increases GH release in rats when given intraventricularly, but also increases GH release directly from dispersed pituitary cells (Ottlecz et al., 1984). Whether PGIz has a functional role in GH regulation remains to be determined. There has been little investi~tion into the effects of PCs on GH secretion in birds. Prostaglandin E, and E, depress GH concentrations and reverse TRH stimulation of GH secretion, but do not affect in vitro GH release from unstimulated pituitary glands (Harvey, 1983a). It is likely that PCs may inhibit GH release by preventing influences.

the

actions

of stimulatory

3. FEEDBACK

There are a number of potential sites for feedback regulation of GH secretion, and these are depicted in Fig. 4 and described below. (i) Ultrashortloop feedback, where GH can suppress its own release, or GRF and/or SRIF can interact with hypothalamic mechanisms to suppress their release. (ii) Shortloop feedback, where GM acts on hypothalamic mechanisms (either on amine metabolism or an hypothalamic releasing hormone secretion) to regulate its release. {iii) Shortloop feedback from the target organ, such as liver somatomedins or thyroid hormones, LEVEL

c _ _ _-_ 1

--__+

EPISODIC STIMULUS

--I

STRESS

Hypothalamus

Median Eminence

Pituitary Gland

Ii

I

t I

01 TRACT

bI

I

I

L

-w--m

GONADS etc.

1

SOMATOMEDINS

I

I

T4

T3 4

,,_,-,,-I

I

THYROID

LIVER

I

__>

1

Target Organs

.s

Fig. 4. Mechanisms regulating the secretion of GH in mammals (highly simplified). Each compartment represents a separate level of control. Arrows joining compartments represent control mechanisms. Where an arrow penetrates a compartment, more detailed information about the mechanism is indicated. Some of the interactions within a compartment are depicted. Arrows: T, stimuiatory mechanism; 7, inhibitory m~hanism.

Control of

GH

acting at the pituitary gland level to modify GH secretion. (iv) Longloop feedback where target organ secretions modify hypothalamic activity. Although feedback regulation of GH secretion has been suspected for some time, it is only recently that feedback control mechanisms have been investigated. The pituitary gland may be a target for feedback regulation. Ultrashortloop feedback of GH at the pituitary gland level seems unlikely, as human GH does not affect GH release from rat pituitary gland cells in culture (Richman et af., 1981). Though Richman ef al. (1981) also failed to suppress basal release of GH with a somatomedin in the culture medium, as mentioned previously somatomedins may act by changing pituitary responsiveness to provocative stimuli, in particular by reducing adenylate cyclase activation following GRF administration (Arimura and Culler, 1985). Thyroid hormones certainly affect GH release from the pituitary gland, but it appears that they promote synthesis and release of GH, as well as increasing GH cell responsiveness to a variety of stimuli (Sonntag er al., 1982). Pituitary cells from hypothyroid rats are less responsive to hpGRF (Dieguez ef al., 1985). There is abundant evidence that feedback regulation of GH occurs at the hypothalamic level. injection of GH into the lateral ventricles of rats suppresses episodic release and basal levels of GH for up to 6 hr after a single administration (Tannenbaum, 1980). Implantation of GH into the median eminence or hypothalamus of prepubertal female rats suppresses pulsatile release of GH and tonically depresses serum GH levels throughout prepubertal development (Advis et nl., 1981). Injections of GH into the lateral ventricles reduces plasma GH levels in rats, an effect not correlated with somatostatjn secretion from the median eminence, suggesting GRF involvement in the feedback response (Fukata et al., 198.5), though in vitro GH and somatomedins stimulate SRIF release from the hypothalamus (Arimura and Culler, 1985). Both human GH and somatomedin C are able to suppress spontaneous GH release when given either centrally or peripherally to rats (Abe et al., 1983). Interestingly, somatomedin C appears to act by stimulating SRIF release from the hypothalamus (Berelowitz et al., 1981). Recently Peterfreund and Vale (1984) have demonstrated an uitrashortloop feedback mechanism regulating SRIF release. In primary cultures of fetal rat hypothalamic cells, SRIF analogues were found to suppress release of endogenous SRIF, though whether the peptides act directly on SRIF release, or whether they act presynaptically to modify neurotransmitter inputs to the SRIF neurones, has not been ascertained. Tanaka and Tsujimoto (1981) suggest that SRIF does have actions on neurotransmitter release in the hypothalamus. Ultrashortloop feedback regulation of GH secretion is suggested by the fact that peripheral administration of large doses of hpGRF, or central administration of smaller amounts, inhibits GH secretion by stimulation of SRIF release into the portal vessels (Arimura pt al., 1984; McCann et al., 1984). The primary site for GH feedback actions may involve central neurotransm~tters. Injections of GH

in vertebrates

243

into rats dramatically reduces content and turnover of dopamine in the median eminence, leading to increased SRIF release, and also that of noradrenaline, which would tend to decrease GRF release (Andersson et al., 1983). In birds the evidence for shortloop feeedback regulation of GH secretion is provided by the observation that longterm administration of hypothalamic extracts (containing GH-releasing activity) to pigeons reduces endogenous hypothalamic GH-releasing activity (Hall and Chadwick, 1984b). It is unlikely that this response is due to ultrashort loop feedback by the exogenous releasing hormones, as their half-life in plasma is very short. Administration of GH itself increases dopamine turnover in the fowl hypothalamus (Hall and Harvey, unpublished observation). However, bovine GH injections apparently do not affect plasma GH levels in both normal and dwarf strains of young chicks (Marsh et al., 1984a). Some evidence for involvement of somatomedin C in regulation of GH secretion in the fowl comes from the work of Huybrechts et a/. (1985) who found that hypophysectomy increases plasma somatomedin C concentrations. Unlike in mammals, thyroid hormones markedly inhibit GH secretion in chickens (Harvey, 1983b). This response may be a reflection of the more important role of TRH in regulating GH secretion in birds (Harvey, 1983a). In vitro, thyroid hormones suppress hypothalamic-induced GH release (unpublished observations). Thyroidal involvement in regulation of GH secretion is also supported by the findings that goitrogens, while suppressing thyroid function, increase plasma GH levels (Harvey, 1983a), thyroidectomy increases plasma GH (Harvey et al., 1983) and that hypothyroid dwarf chickens have increased plasma GH concentrations (Scanes et al., 1983b). Feeding thyroid hormones in the diet of normal, sex-linked and autosomal dwarf chickens reduces plasma GH levels (Leung et al., 1984; Marsh et al. 1984b). 4. OTHER

HORMONES

Gonadal hormones are believed to exert a permissive effect on GH secretion in mammals, and sex steroids affect GH secretion in humans, rodents and ruminants (see Jansson et al., 1984). Oestrogens have stimulatory effects on GH release. Thus, on the day of oestrus and in ovari~tomized rats primed with oestrogen plasma GH levels are increased, and oestrogens increase sensitivity of the pituitary gland to stimuiatory influences (Ojeda et al., 1983). Oestrogens also enhance the inhibitory activity of angiotensin on GH release at the pituitary gland (Steele et al., 1982). In rats the pulsatile release of GH is sexually differentiated and pulses are smaller and less frequent, though with higher base-line levels, in females compared to males. Neonatal gonadectomy produces changes in the pulsatile pattern of GH secretion that is established about the time of puberty so as to lessen the differences between the sexes, and these differences are re-established by appropriate steroid replacement. It is possible that differences in body growth may result from sexual differentiation of GH secretory patterns (Jansson ef ul., 1984). The role

T. R.

234

HALL et al.

of adrenal steroids and dexamethasone in increasing pituitary gland responsiveness to GRF has been mcntlclned previously. In addition corticosteroids may incrcasc GH release by reducing specific binding of SRI F through ;I reduction in receptor availability (Schonhrunn. 1982). Gastrointestinal hormones also cfYcct (iFI secretion. though CCK, VIP, substance P, bombcsln. etc.. probably affect GH due to their roles as nellromodulators or releasing hormones in the hypothalamus (see above). Pancreatic homones may play ;L role in the regulation of GH release as part of the mechanism controlling intermediary metabolism. Insulin administration, probably as a result of the induced hqpoglycacmia. markedly elevates GH levels (Sonntag (‘I r/l.. 1982). Glucagon conversely suppressc\ GH rclcasc. probably by stimulating SRIF rclcasc (Katakami (31(II.. 1983), though whether endogcnou5 pancreatic glucagon has direct actions on the hypothalamus. whether exogenous glucagon mimicks the action< of ;I hypothalamic glucagon, or whether the response is merely due to induced hyperglycaemia is uncertain. In birds. the gonadal steroids may also play a role in the regulation of GH secretion. Chicken pituitary glands prcincubated with testosterone, oestrogen or progchtcronc show reduced responsiveness to the stimulator! actions of TRH or hypothalamic extracts irz rirw. though the steroids apparently do not affect basal output of the hormones (Hall et al., 1984e,f,g). Tcstostcronc implants into chickens and turkeys reduce plasma GH concentrations (Harvey, 1983a). Both insulin and glucagon administration reduce plasm;t GH conccntratlons in chickens and ducks, and these response arc not due to changes in plasma gluco~ or free fatty acid concentrations. The effects of pancreatic hormones arc probably mediated by specific ncurochcmical alterations in the hypothalamus (unpub!ished observations). Stimulation of the pituitary-adrenal axis and corticosterone administration also lower plasma GH concentrations (Harvey. 1983a). The cffccts of steroids in altering pituitary sensitivity to provocative stimuli may be a common feature 111the vertcbratcs. Oestradiol-17fi and testostcronc v+crc found to increase the sensitivity of the terrapin (C/I~JXJ~~IJ~.,\ picfa) pituitary gland to the stimulatory etfccts of hypothalamic extract on GH rclcasc irk ri[ro (Hall et crl.. 1978). In addition, steroids may :tiTcct GH secretion by actions on the hypothalamus. Certainly. oestrogen pretreatment has been found to aff‘cct turnover of noradrenaline and serotonin in the hypothalamus of the domestic fowl (Hall e; al., 1986a) and clomiphene citrate, a non-steroidal nntiocstrogcn. aff‘ccts serotonin turnover in the goldtish hypothalamus (Olcese et al., 1984). These amincs arc knoun to be involved in hypothalamic regulation of GH secretion.

f;. VIETABOLIC

FACTORS

It is well known that. in some mammalian species, including man. hyperglycaemia decreases and hypoglycacmla increases GH secretion. While at least part of the response may be due to changes in insulin and glucagon secretion (see above). Lengyel et al. (1984)

have shown in vitro that glucose itself can affect the release of SRIF from hypothalamic fragments. However, rats made diabetic with streptozotocin show exaggerated responsiveness to hpGRF stimulation of GH secretion in spite of the considerably higher blood glucose concentrations (Locatelli et al., 1984a). However, Masuda et al. (1985) have shown that preloading with glucose reduced plasma GH responses to hpGRF in young men, with a suggestion that the induced hyperglycaemia stimulated the secretion of SRIF. Free fatty acid levels may regulate GH output (Arimura and Culler, 1985) since drugs that reduce free fatty acid levels increase GH secretion in man (Quabbe et al., 1983a) and in sheep (Radekopp et al., 1984). Pretreatment with free fatty acids reduces responses to hpGRF in man (Imaki et al., 1985). Ketone bodies, such as fl-hydroxybutyrate, prevent the rise in GH associated with reduced free fatty acid levels (Quabbe et al., 1983b). Undoubtedly the effects of intermediary metabolites on GH secretion are complex, though their physiological significance is unclear. Chronic nutritional deprivation is accompanied by elevated concentrations of GH, and the response appears to be related to the amount of protein provided in the diet. Acute food withdrawal may not alter GH secretion in many mammalian species. Infusion of the amino acid, arginine, stimulates GH secretion (Sonntag et al., 1982). The mechanisms producing these changes in GH output are not known, though Delitala er al. (1982) have indicated that arginine-induced GH secretion may act through a cholinergic mechanism, since the response is blocked by the antagonist pirenzepine. The plasma concentration of GH is profoundly affected by nutrition in the domestic fowl and turkey (Proudman and Opel, 1981; Harvey, 1983a). Though growth is retarded in intermittently-fed chickens, plasma GH levels remain elevated (Nir et al., 1983). Isocaloric diets deficient in protein specifically increase plasma GH, which is inversely related to the protein intake (Scanes et al., 198 1; Sommerville et al., 1985a). Interestingly, a tryptophan-deficient diet, which would reduce brain serotonin concentrations as it is an essential amino acid, also increases plasma GH levels (Carew et al., 1983). Arginine has no effect on plasma GH concentrations (Harvey, 1983a). Free fatty acids may also regulate GH secretion. Scanes et al. (1983a) found that oleic acid injections reduced plasma GH in young domestic fowl, indicating a probable negative feedback regulation system. However, Foltzer et al. (1986) found stimulation of GH secretion following infusion of oleic acid into ducklings. The reason for these contrary results is not known. A reduced intake of dietary phosphorus produces reduced somatic growth and a temporary reduction in plasma GH levels, GH recovering by the third day of treatment. Similarly low Cal+ diets reduce plasma GH levels for a short period of time (Sommerville et al., 1983, 1985a,b). Chicks reared on a low Ca*+ diet have low plasma GH for the first 15 days of treatment, but GH levels are normal thereafter. However, GH responses to TRH and hpGRF are similar in both normal and Ca’+ -deprived birds. A Ca’+ chelator (EDTA), verapamil and calmodulin inhibitors

Control Acutely reduce basal GH concentrations fowl (Harvey er al., 1984~). 6. EXTERNAL

of GH

in domestic

FACTORS

Both stress (handling, trauma, aversive stimuli, some anaesthetics, haemorrhage, etc.) and exercise stimulate GH release in many mammals, though stress reduces GH secretion in rats (Sonntag et a/., 1982). Changes in GH release in rats are probably not due to changes in catecholamine activity in the hypothalamus, since chemical lesions induced by 6-hydroxydopamine fail to prevent stress suppression of GH (Day et al., 1983). Many mammals, including man, show daily rhythms of activity and hormonal secretory patterns, some of which are spontaneous and others of which may be entrained to various signals (Weitzman et al., 1981). GH secretion is markedly elevated in humans at night, during the sleep period. This episodic burst of GH is entrained to the onset of sleep rather than light-dark cycles, as it is readily reversible (Sonntag et al., 1982). The Table I. Factors Factor ~.~_~~ Neurotransmitters Dopamine Noradrenaline

Adrenaline Serotonin Acetylcholine Histamine GABA Peptides TRH GRF SRIF Endorphins VIP Bomb&n CCK Substance P Angiotensin II Motilin Secretin GIP GRP Neurotensin CRF LHRH Calcitonin Hormones Insulin Glucagon (rat) Glucagon (human) Oestradiol Testosterone Progesterone Glucocorticoids T4IT3 Somatomedin

affecting

Mammals

It If (I, t1

in

vertebrates

245

activity-rest cycle also affects pituitary responsivity, since TRH is able to stimulate GH secretion in humans only in the evening and not in the morning, unless the activity-rest cycle is reversed (Caroff et al., 1984). A shortened photoperiod does not affect GH secretion in hamsters (Klemcke et al., 1983). However, GH secretion in young reindeer shows an annual cycle, with a peak in late winter which may be related to feed intake (Lyg and Jacobsen, 1982). In birds, various stresses such as ether anaesthesia, cold stress and adrenal hormones (evoked during stress) reduce plasma GH levels (Harvey, 1983a). Ambient temperature and other seasonal factors apparently affect annual GH secretory profiles in several species of birds (Scanes et al., 1983a). Availability of water also affects GH secretion. In the turkey, GH concentrations are elevated after removal of drinking water (Proudman and Opel, 1981). While water deprivation does not affect plasma GH in ducks (Harvey and Phillips, 1980) or chickens, it reduces subsequent pituitary responsiveness to hypothalamic stimulation (Harvey et al., 1984a). In teleosts, osmotic factors apparently affect GH

GH release in mammals

Hypothalamic effects

a,

Hypothalamic effects

Birds

1 t

JSRIF OL, TSRIFJGRF a,tGRF BlSRIF TG?RF JSRIF (1GRF) (Endorphins?)

and birds

&F TSRIF

ff

&F?

receptor? (ISRIF?) (ISRIF?) NT

TSRIF TSRIF tSRIF (hyperglycaemic effect?)

It + + +(GRF) +(GRF) -(GRF) 1 TSRIF?

NT NT NT NT NT NT NT 0 NT

(JSRIF?) TSRIF Cholinergic -(TRH, -(TRH. -(TRH,

GRF) GRF) GRF) _ -

Key: t increases GH secretmn (tt strong stimulator); 1 decreases GH inhibitor); ( ) inconclusive results, or unsubstantiated observation; 71 inhibition reported; + increases pituitary sensitivity to stimuli; sensitivity to stimuli; 0 no reported effects; ? hypothalamic action, described; NT not tested. Note that this table is not definitive, based mainly on work in rat and interpretation based on the weight of evidence. Other species can responses.

SRIF?

secretion (14 strong both stimulation and decreases pituitary but mechanism not chicken, and is our show very different

T. R. HALL et al.

246

secretion. Eel pituitary glands release more GH in low osmolar medium, and increasing salinity depresses synthesis of GH in Poeciiia pituitary glands (Ball, 1981). Hall and Chadwick (1978) showed that adaptation of eels to sea-water from fresh water produced a fall in pituitary GH content with a gradual return to normal by 8 weeks of adaptation. However, the pituitary glands of sea-water-adapted eels release less GH, are less responsive to hypothalamic stimufation, and possess reduced hypothalamic GH-releasing activity, compared to freshwater-adapted control eels. CONCLUSIONS

Table 1 and Fig. 4 summarize some of the factors that are known to affect GH secretion in mammals and birds. Other vertebrate groups, though probably showing similar m~hanisms, are not included as too little information is avaiiable. The information contained therein is not defmitive, as many contradictory examples can be found in the scientific literature. A few generalizations can be made. It is probable that the hypothalami of all vertebrate species contain GH-releasing and GH release-inhibiting peptides, probably similar to the mammalian peptides. In addition other peptides, particularly TRH, may play a greater or lesser role in the regulation of GH secretion. Release of these peptides is controlled by the hypothalamic neurotransmitters, which are unlikely to have major effects themselves at the pituitary gland level. However, it is strikingly apparent that the avian and mammalian neurochemical regulatory processes differ in almost every respect, and where most neurotransmitters stimulate mammalian GH release, they inhibit GH release in birds. One glaring omission from the publjshed literature concerns the mechanism through which these transmitters operate, i.e. GRF, SRIF or other peptides. The recent development of GRF radioimmunoassays should soon shed light on this problem. A further general regulatory mechanism can be proposed. Steroids appear to act by modifying pituitary (and hypothalamic?) responsiveness to secretagogues rather than directly affecting hormone release. Finally, GH secretion is highly susceptible to ~rturbations from external signals, such as food and water availability and various specific and non-specific stresses. The osmotic effects, which may be of importance in euryhaline teleosts, is also seen in modified form in birds. Because of the metabolic role of GH, it is important for an animal to be able to respond to threatening situations within its ecological niche.

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