Cortistatin mimics somatostatin by inducing a dual, dose-dependent stimulatory and inhibitory effect on growth hormone secretion in somatotropes

Cortistatin is a recently discovered neuropeptide that is structurally related to somatostatin, the classic inhibitor of growth hormone (GH) release. Cortistatin binds with high affinity to all five somatostatin receptors (sst1–5), and, like somatostatin, cortistatin inhibits in vivo GH release in man and rats. In this report, we compared the in vitro actions of cortistatin and somatostatin using primary pig pituitary cell cultures. In this species, we have previously reported that somatostatin not only inhibits GH-releasing hormone (GHRH)-stimulated GH release at high doses, but also stimulates basal GH release at low (pM) doses, a dual response that is markedly dependent on the subpopulation of pituitary somatotropes examined. Results reported herein demonstrate that cortistatin closely mimics the dose-dependent inhibitory and stimulatory effects of somatostatin on GH secretion. As cortistatin, unlike somatostatin, binds to the human receptor for ghrelin/GH secretagogs (GHS-R), we also investigated whether cortistatin stimulates GH release through this receptor by using a synthetic, short form of cortistatin, cortistatin-8 (CST8), which lacks the sst-binding capacity of full-length cortistatin but retains its GHS-R-binding capacity. Interestingly, CST8 stimulated GH release only at low doses (10−15 M), and did not reduce GH secretion stimulated by GHRH, ghrelin, or low-dose, full-length cortistatin, yet it counteracted that induced by a nonpeptidyl GHS, L-163 255. Taken together, our results indicate that the dual, inhibitory and stimulatory effects of cortistatin on GH release closely parallel those of somatostatin and are probably mediated by the same receptor(s) and signaling pathway(s) for both peptides. Furthermore, they suggest that the pathway(s) activated by cortistatin (and somatostatin) to stimulate GH release are not initiated by GHS-R activation.

Download Full-text

A possible relationship between serum transferrin, growth hormone secretion and height velocity in children

Acta Endocrinologica ◽

10.1530/acta.0.0930134 ◽

1980 ◽

Vol 93 (2) ◽

pp. 134-138 ◽

Cited By ~ 4

Author(s):

M. Donnadieu ◽

R. M. Schimpff ◽

P. Garnier ◽

J. L. Chaussain ◽

J. C. Job

Keyword(s):

Growth Hormone ◽

Growth Regulation ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Height Velocity ◽

Obese Children ◽

Gh Secretion ◽

Growth Promoting

Abstract. Since transferrin (Tf) in vitro has a growth-promoting activity and is associated with NSILA properties, the aim of this work was to study in vivo the relationships between Tf, somatomedin activity (SM), growth hormone (GH) secretion, and height velocity in children. An iv infusion of ornithine hydrochloride was given to 23 controls; the induced rise of GH was accompanied by a simultaneous fall of SM (r = −0.711, P < 0.001) and was preceded by a fall of Tf (r = −0.610, P < 0.01). In 17 obese children SM was within the normal range, when Tf levels were higher and arginineinduced GH peaks lower than in the controls, and a negative correlation was found between Tf basal levels and GH peaks (r = −0.608, P < 0.01). In 9 children with confirmed hypopituitarism the Tf levels were significantly lower than in the controls. In 14 children with confirmed or suspected hypopituitarism a single im injection of hGH (6 mg) failed to induce Tf variations over 24 h. In 39 of these children the height velocity was significantly correlated with Tf basal levels (r = 0.701, P < 0.001). These data suggest that transferrin is involved in growth regulation, and that GH secretion is related to transferrin levels by a feed-back mechanism.

Download Full-text

Glucocorticoid modulation of growth hormone secretion in vitro. Evidence for a biphasic effect on GH-releasing hormone mediated release

Acta Endocrinologica ◽

10.1530/acta.0.1140465 ◽

1987 ◽

Vol 114 (4) ◽

pp. 465-469 ◽

Cited By ~ 21

Author(s):

Gian Paolo Ceda ◽

Robert G. Davis ◽

Andrew R. Hoffman

Keyword(s):

Growth Hormone ◽

Prolonged Exposure ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Inhibitory Effect ◽

Pituitary Cells ◽

Gh Secretion ◽

Glucocorticoid Action

Abstract. Glucocorticoids have been shown to have both stimulatory and suppressive effects on GH secretion in vitro and in vivo. In order to study the kinetics of glucocorticoid action on the somatotrope, cultured rat pituitary cells were exposed to dexamethasone for varying periods of time. During short-term incubations (≤ 4 h), dexamethasone inhibited GHRH and forskolin-elicited GH secretion, but during longer incubation periods, the glucocorticoid enhanced both basal and GHRH-stimulated GH release. The inhibitory effect of brief dexamethasone exposure was also seen in cells which previously had been exposed to dexamethasone. In addition, growth hormone secretion from cultured rat and human somatotropinoma cells was inhibited by a brief exposure to dexamethasone. Thus, the nature of glucocorticoid action on the isolated cultured somatotrope is biphasic, with brief exposure inhibiting, and more prolonged exposure stimulating GH secretion.

Download Full-text

Growth hormone secretion in the guinea-pig

Journal of Endocrinology ◽

10.1677/joe.0.1240371 ◽

1990 ◽

Vol 124 (3) ◽

pp. 371-380 ◽

Cited By ~ 14

Author(s):

B. Gabrielsson ◽

K. M. Fairhall ◽

I. C. A. F. Robinson

Keyword(s):

Growth Hormone ◽

Guinea Pig ◽

Guinea Pigs ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Physiological Control ◽

Gh Secretion ◽

Dose Dependent Fashion ◽

Growth Promoting ◽

Dose Dependent

ABSTRACT The guinea-pig is unusual in that it continues to grow at a normal rate after hypophysectomy. Although its pituitary gland appears to contain a GH, this has not been isolated or characterized, and nothing is known about its secretion or physiological control. We have identified guinea-pig GH, established a sensitive heterologous radioimmunoassay and adapted our automatic blood microsampling method to study spontaneous GH secretion in this species. In male guinea-pigs, GH is released in an episodic pattern, reminiscent of the rat. Large multicomponent pulses of GH secretion occur every 3–4 h between periods of low or undetectable GH release, whereas most females showed a more uniform pulsatile pattern with pulses every 1–2 h. GH was released in response to GH-releasing factor (GRF) injections (2, 10 or 20 μg [Nle27]-GRF(1–29)NH2) in a dose-dependent fashion, and i.v. infusion of somatostatin (50 μg/h) blocked spontaneous GH pulses, eliciting a rebound release (from 2·0±0·8 (s.e.m.) to 36±17 μg/l 30 min after stopping the infusion). Infusions of a GH-releasing hexapeptide (100 or 400 μg/h for 4 h) also released GH. These results provide the first description of the pattern of GH release in the guinea-pig, and suggest that the striking episodic pattern is controlled by the same hypothalamic peptides that regulate GH in other species. Since the guinea-pig grows well in the absence of GH, this species may use GH for its metabolic, rather than growth-promoting actions. The guinea-pig may well prove a useful model, now that methods are available for studying its endogenous GH secretion. Journal of Endocrinology (1990) 124, 371–380

Download Full-text

STUDIES ON GROWTH HORMONE SECRETION II. STIMULATION BY PROSTAGLANDINS IN VITRO

Acta Endocrinologica ◽

10.1530/acta.0.0680355 ◽

1971 ◽

Vol 68 (2) ◽

pp. 355-362 ◽

Cited By ~ 27

Author(s):

F. Hertelendy

Keyword(s):

Growth Hormone ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Absolute Amount ◽

Prostaglandin E ◽

High Concentration ◽

Gh Secretion ◽

Molar Basis ◽

Energy Dependent

ABSTRACT Hemisected rat anterior pituitaries were incubated in KRB (pH 7.4) containing glucose (1 mg/ml) and BSA (1 mg/ml) and the release of growth hormone (GH) was measured by radioimmunoassay. Prostaglandin E1 and E2 (1 μg/ml each) increased GH concentration in the medium by 298 % and 266 % respectively over controls during a one-hour incubation period. On molar basis prostaglandins proved to be at least a thousand times more potent stimulants of GH secretion than theophylline or dibutyryl cyclic AMP. This response was drastically reduced by preincubating the pituitary explants in the presence of EGTA in a calciumfree medium. Addition of calcium (1 mm) restored the relative GH response to PGE1 though the absolute amount of GH released was considerably less than that observed without EGTA treatment. Hormone secretion was potentiated by high concentration of K+ (54 mm) which in itself significantly stimulated GH release. 2,4-Dinitrophenol almost completely abolished PGE1 stimulated GH release indicating that the latter is an energy dependent phenomenon. The possible mechanism by which prostaglandins stimulate GH secretion and the interaction of ions in the secretory mechanism are discussed.

Download Full-text

Long-term in-vitro maintenance of growth hormone secretion from human somatotrophinomas with cortisol, and its effects on growth hormone-releasing factor

Journal of Endocrinology ◽

10.1677/joe.0.1140503 ◽

1987 ◽

Vol 114 (3) ◽

pp. 503-509 ◽

Cited By ~ 2

Author(s):

M. Daniels ◽

M. C. White ◽

P. Kendall-Taylor

Keyword(s):

Growth Hormone ◽

Dose Range ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Test Dose ◽

Gh Secretion ◽

Term Maintenance ◽

Secretion Rates

ABSTRACT The effect of cortisol (206 nmol/l) on GH secretion from enzymatically dispersed human somatotrophinoma cells in long-term culture was studied using adenomas from 13 patients with acromegaly. Basal GH secretion from cultures of three out of five tumours measured during periods of 4 hours declined to < 10 μu. GH/culture within 21 days. Secretion from two other tumours measured during 24 h also declined but GH concentrations were still readily detectable (> 100 μu./culture) by 28 or 58 days after cell dispersal. The decline in GH secretion was reversed in all seven tumours when cultures were maintained in cortisol-supplemented medium (CM), 4-h secretion rates being increased or retained at ≥ 100 μu./culture for as long as the studies were continued (range 18–291 days), and 24-h secretion rates at > 1000 μu./culture (range 28–58 days). GH secretion and content from cultures of two additional somatotrophinomas were increased by treatment with cortisol for 5 or 9 days but there was no concomitant effect on cell number. During long-term maintenance of cultures in CM (range 5–40 days), cortisol partially or completely blocked the 4-h GH response to a test dose of GH-releasing factor (GRF) (20 nmol/l) in five out of six tumours, and to a dose range of GRF (0·01–20 nmol/l) in two of them. However, when cultures maintained in this way (range 7–89 days) were rinsed and acute studies performed in medium without added cortisol, a significant (P < 0·05) stimulatory effect of GRF either at a test dose of 20 nmol/l or with a dose range (0·02–20 nmol/l) was observed in all six tumours tested. In conclusion, long-term maintenance of human somatotrophinoma cells in medium supplemented with cortisol (206 nmol/l) prevents the early decline in GH secretion and extends their functional lifespan for several weeks or months. However, the stimulatory effects of GRF during such treatment are usually partially or completely blocked in the presence of medium containing cortisol but restored when cortisol is excluded from the medium. J. Endocr. (1987) 114, 503–509

Download Full-text

EFFECT OF CHICKEN HYPOTHALAMUS ON PROLACTIN AND GROWTH HORMONE SECRETION IN MALE CHICKENS

Journal of Endocrinology ◽

10.1677/joe.0.0820193 ◽

1979 ◽

Vol 82 (2) ◽

pp. 193-197 ◽

Cited By ~ 18

Author(s):

S. HARVEY ◽

C. G. SCANES ◽

A. CHADWICK ◽

G. BORDER ◽

N. J. BOLTON

Keyword(s):

Growth Hormone ◽

Medulla Oblongata ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Pituitary Cells ◽

Plasma Prolactin ◽

Gh Secretion ◽

Brain Tissues

SUMMARY The effects of a chicken hypothalamic extract (HE) on the secretion of prolactin and growth hormone (GH) in vivo have been investigated by radioimmunoassay in the domestic fowl. Different i.v. doses of HE (0·25–25 HE equivalents/kg body weight) had no effect on GH secretion in conscious or anaesthetized cockerels. In both groups of birds the concentration of plasma prolactin was significantly increased within 10 min of administration of the extract. Extracts of other brain tissues (cerebral cortex, cerebellum and medulla oblongata) had no stimulatory effect on prolactin or GH secretion. Release of both prolactin and GH by dispersed pituitary cells and by hemipituitary glands in vitro was enhanced following incubation with HE (5 hypothalami equivalents/ml) or with single whole hypothalami respectively. Other brain tissues (cerebellum, optic lobes and medulla oblongata) had no effect on the concentration of prolactin or GH released by incubated hemipituitary glands.

Download Full-text

Inhibition of growth hormone secretion by activin A in human growth hormone-secreting tumour cells

Acta Endocrinologica ◽

10.1530/acta.0.1240666 ◽

1991 ◽

Vol 124 (6) ◽

pp. 666-671 ◽

Cited By ~ 5

Author(s):

Masafumi Kitaoka ◽

Kohji Takano ◽

Yuji Tanaka ◽

Itaru Kojima ◽

Akira Teramoto ◽

...

Keyword(s):

Growth Hormone ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Human Growth ◽

Activin A ◽

Tumour Cells ◽

Free Calcium ◽

Gh Secretion

Abstract. Effect of activin A on growth hormone secretion was studied in primary culture of 8 human GH-secreting adenomas, which were responsive to TRH in vivo. When studied in vitro, basal GH secretion was reduced in all cases when cells were pre-incubated for 48 h with activin A at a concentration of 5×10−9 mol/l or greater. Pretreatment of GH-secreting cells with 1× 10−9 mol/l activin A did not affect either basal secretion or cellular content of GH. These tumour cells also responded to TRH in vitro and the GH response to TRH was completely blocked in cells pretreated with activin A. Activin A slightly reduced the increase in cytoplasmic free calcium concentration induced by TRH. Furthermore, pretreatment of the cells with activin A attenuated GH secretion induced by A23187 or 12-O-tetradecanoyl phorbol-4-acetate, agents which bypass receptor-mediated generation of second messengers. These results indicate that activin A inhibits GH secretion by directly acting on human GH-secreting cells and that activin A inhibits the action of TRH by acting on multiple steps in the messenger system.

Download Full-text

Ghrelin-induced growth hormone secretion in humans

Acta Endocrinologica ◽

10.1530/eje.0.143r011 ◽

2000 ◽

pp. R11-R14 ◽

Cited By ~ 162

Author(s):

R Peino ◽

R Baldelli ◽

J Rodriguez-Garcia ◽

S Rodriguez-Segade ◽

M Kojima ◽

...

Keyword(s):

Growth Hormone ◽

Total Dose ◽

Dose Response ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Prolactin Secretion ◽

Gh Secretion ◽

Relevant Dose

Ghrelin is a novel growth hormone (GH) releaser acylated peptide that has recently been purified from stomach, and which potently binds to the GH secretagogue receptor. Ghrelin releases GH in vitro and in vivo in animal models, however its actions, potency and specificity in humans are unknown. In the present study, 12 healthy subjects were studied: 6 underwent four tests with ghrelin administered i.v. at the dose of 0 (placebo), 0.25, 0.5 and 1 microg/kg which corresponds to 0, 18, 37 and 75 microg total dose. A further 6 volunteers underwent two tests on different days with ghrelin at the dose of 3.3 or 6.6 microg/kg which corresponds to 250 microg and 500 microg total dose. Ghrelin-mediated GH secretion showed a dose-response curve, in which 1 microg/kg was the minimally effective dose in some individuals, but not as a group. On the contrary, the total doses of 250 microg and 500 microg elicited a powerful GH secretion, with a mean peak of 69.8+/-9.2 microg/l and 90.9+/-16.9 microg/l respectively, and areas under the curve of 4435+/-608 and 6125+/-1008 microg/l per 120 min respectively. All of them statistically significant vs placebo and vs the 1 microg/kg dose. Ghrelin administration also elicited a relevant dose-response mediated prolactin secretion suggesting no specificity of its actions. No relevant side effects were observed with ghrelin apart from a hyperhydrosis episode in two individuals tested with the higher ghrelin doses. In conclusion, ghrelin is a potent releaser of GH in normal individuals, with a dose-response pattern of operation. No saturating dose was observed.

Download Full-text