EFFECT OF PIMOZIDE ON LEVODOPA-INDUCED GROWTH HORMONE RELEASE IN MAN

SUMMARY. Serum growth hormone (GH) behaviour after levodopa administration was measured in twelve healthy subjects both in basal conditions and after a 4 day course of pimozide (4 mg daily), a specific blocker of dopamine (DA) receptors. In addition, fasting plasma GH was measured on the first, second and third day of treatment. No significant difference was found between GH response to levodopa in basal conditions and after pimozide; moreover, fasting GH was uninfluenced by pimozide.     

ADDITIVE EFFECTS OF GROWTH HORMONE RELEASING FACTOR AND INSULIN HYPOGLYCAEMIA ON GROWTH HORMONE RELEASE IN MAN

We have measured GH and PRL changes following separate and combined administration of insulin and GH releasing factor (GRF) in six normal males. Peak GH responses to separate administration of insulin and GRF were comparable (71.4 +/- 10.2 vs 70.1 +/- 27.7 mU/l; mean +/- SEM). However, the peak GH response following combined administration was significantly higher (120.8 +/- 29.7, P less than 0.05) as was the total GH released as calculated by measuring the area under the curve (P less than 0.05). In contrast the PRL response to hypoglycaemia was not altered by the combined administration of insulin and GRF. This effect was not due to any direct action of hypoglycaemia or insulin at pituitary level since basal and 10(-8) M GRF stimulated GH release from rat anterior pituitary cells in vitro was not influenced by varying glucose and insulin levels. Our findings support the hypothesis that GRF and insulin-induced hypoglycaemia release GH via different pathways which are, at least in part, additive.     

METOCLOPRAMIDE INDUCED GROWTH HORMONE RELEASE IN HYPOGONADAL MALES

The growth hormone (GH) response to 10 mg intravenous metoclopramide (MCP) ('Maxolon'--Beecham Laboratories) was determined in ten hypogonadal adult males. All the subjects responded with a peak growth hormone level greater than 14 mU/l within 1 hour of administration of MCP. Seven normal adult males did not respond to MCP administration. It is concluded that MCP stimulation may be a useful test for both prolactin and growth hormone reserve in hypogonadal males.     

THE INFLUENCE OF OCTREOTIDE TREATMENT ON PULSATILE GROWTH HORMONE RELEASE IN ACROMEGALY

The pulsatile release of GH was investigated in eight active acromegalic patients before and during a subcutaneous infusion of 300 micrograms octreotide/24 h for 4 weeks. The number of GH pulses increased from a basal value of 14.4/24h to 16.3/24h during octreotide therapy. At the same time the mean GH concentration, valley concentration, peak height and amplitude decreased significantly. The inhibitory effect of octreotide on pulse characteristics did not depend on the time of day. IGF-I levels also decreased significantly; in five patients normal levels were reached. IGF-I levels correlated significantly with the mean GH level (r = 0.714, P less than 0.001), mean valley concentration (r = 0.697, P less than 0.001) and, to a lesser extent, area under the curve (r = 0.436, P = 0.033), but not the number of pulses. Plasma octreotide levels did not correlate with pulse parameters. In all but one patient a circadian rhythm was present during both the basal study and octreotide therapy. Compared with surgically treated acromegalics, the number of GH pulses was higher in untreated and octreotide-treated patients. This study demonstrates the pulsatile release of GH in active acromegaly both before and during octreotide therapy. This result suggests that endogenous GHRH is important for the generation of GH pulses in this disease.     

INHIBITORY EFFECT OF CIMETIDINE ON L-DOPA-STIMULATED GROWTH HORMONE RELEASE IN NORMAL MAN

Some evidence suggests the existence of a histaminergic influence on GH secretion in animals and man. We used cimetidine, a specific H₂-receptor antagonist, to study the possible interference of H₂-receptor blockade on plasma GH release by L-dopa and on PRL inhibition by L-dopa in normal man. Seven healthy normal male volunteers aged 23–36 years received a single oral dose of L-dopa (500 mg) or an i.v. bolus of cimetidine (300 mg) or both (L-dopa 30 min before cimetidine). Blood samples were taken at various times over 2 h and plasma GH and PRL levels measured. Cimetidine alone did not alter basal plasma GH values; L-dopa elicited the well-known GH releasing effect with peak values at 75 min (15.65 ± 2.8 ng/ml); cimetidine injected 30 min after L-dopa ingestion significantly blunted the GH response to L-dopa and peak values (4.7 ± 1.6 ng/ml) were delayed to 105 min. Cimetidine provoked a rapid rise in plasma PRL with the peak value of 15 ± 3 ng/ml at 15 min, followed by a return to near basal values in 90–120 min. L-Dopa completely inhibited the PRL response to cimetidine. We conclude that there is an inhibitory influence of the H₂-receptor antagonist cimetidine on GH release by L-dopa. This, together with the action of cimetidine on PRL secretion (with or without L-dopa), suggests a possible antidopaminergic effect of H₂-receptor blockade at the level of the central nervous system.     

INHIBITORY EFFECT OF SEROTONIN ANTAGONISTS ON GROWTH HORMONE RELEASE IN ACROMEGALIC PATIENTS

We evaluated the effect of the serotonin antagonists cyproheptadine (Cypro) and methysergide (Methy) on growth hormone secretion in six patients with acromegaly. Two days administration of Cypro deceased the plasma GH concentration during oral glucose tolerance tests in four of the six patients evaluated; 2 days administration of Methy reduced the plasma GH levels of only one of the four patients evaluated. The one patient whose palsma GH concentration was lowered by Methy, did not have a decerase in plasma GH concentration after Cypro administration. Acromegalic patients have normal serum serotonin concentration and normal 5-hydroxyindoleacetic acid excretion. If Cypro lowers plasma GH by antagonizing serotonin, our data would suggest that serotoninergic neruonal pathways are important in the regulation of pituitary GH secretion in some patients with acromegaly.     

THE CHARACTERIZATION OF GROWTH HORMONE RELEASE INHIBITING HORMONE-LIKE IMMUNOREACTIVITY IN NORMAL URINE

SUMMARY. Using a previously described radioimmunoassay for growth hormone release inhibiting hormone (GH-RIH), the presence of GH-RIH-like immunoreactivity in urine has been characterized by demonstrating mobility identical to synthetic GH-RIH standard on two sephadex gel chromatographic systems, and parallelism of dilutions of the sephadex fractions with synthetic GH-RIH. Furthermore, 74% of the sephadex fraction cross-reacting in the immunoassay bound to antibody conjugated to sepharose and could be eluted by 1 M acetic acid. This immunospecific eluate showed identity with synthetic GH-RIH on both ion exchange and thin layer chromatography. Thus GH-RIH-like immunoreactivity is present in normal urine; this may have potential relevance in the search for a physiological role for this peptide.     

SPECIFIC INHIBITION BY SOMATOSTATIN OF GROWTH HORMONE RELEASE AFTER HYPOGLYCAEMIA IN NORMAL MAN

In normal man, synthetic linear somatostatin (growth hormone-release inhibiting hormone) inhibits the growth hormone response to insulin induced hypoglycaemia, but has no influence on plasma levels of cortisol, prolactin, TSH and FSH.     

STIMULATION BY GROWTH HORMONE OF SOMATOSTATIN RELEASE FROM THE RAT HYPOTHALAMUS IN VITRO

SUMMARY Growth hormone (GH) has been shown to cause a dose-dependent increase in the release of immunoreactive somatostatin from the rat hypothalamus in vitro, thus providing further evidence that GH may be involved in a ‘short loop’ feedback, controlling its own secretion via hypothalamic somatostatin release.     

SYNTHESIS AND RELEASE OF HUMAN GROWTH HORMONE FROM LUNG CARCINOMA IN CELL CULTURE

Cells obtained from the lung carcinoma Summary of a patient with hypertrophic pulmonary osteoarthropathy were maintained in culture for 4 months. Synthesis of human growth hormone (H.G.H.) in vitro was demonstrated by the incorporation of label from ¹⁴C-leucine into material with the characteristics of H.G.H. on gel filtration and paper chromatography. Release of immunoreactive human growth hormone (I.R.H.G.H.) from the cultured cells was stimulated by theophylline and dibutyryl cyclic-3',5'-adenosine monophosphate. The patient was found to have a diabetic glucose-tolerance test and abnormally high plasma concentrations of I.R.H.G.H. which returned to normal after resection. The tumour contained a higher concentration of I.R.H.G.H. than the adjacent lung. These findings are consistent with synthesis and release of H.G.H. by the carcinoma in vivo.     

STIMULATION OF GROWTH HORMONE RELEASE BY LUTEINIZING HORMONE-RELEASING HORMONE AND MELANOCYTE-STIMULATING HORMONE-RELEASE INHIBITING HORMONE IN THE HYPOPHYSECTOMIZED RAT BEARING AN ECTOPIC PITUITARY

Intrajugular administration of LHRH (0-6 and 1-2 mug) in hypophysectomized rats which received renal grafts of anterior pituitary induced a small but significant rise in plasma GH 5 and 10 min post-treatment. LHRH, at the same dose levels, was ineffective in weight-matched intact controls. MIF, at the dose of 1-2 mug, induced a slight GH rise 5 min after treatment in hypophysectomized trasnplanted rats, while it was ineffective in intact controls. Unlike the two hypothalamic peptides, alpha-MSH (0-6 and 1-2 mug) was ineffective as a GH-releaser in both transplanted and intact rats.     

雌二醇对动情间期切除卵巢母羊黄体生成激素脉冲分泌的抑制作用

12只动情间期母羊切除卵巢后,根据随机皮下植入或不植入E_2而分为二组。通过颈静脉插管每5～10分钟采血一次,连续8～9小时,分离血浆作LH放免测定。实验组的平均LH基础分泌水平和LH脉冲幅高比对照组显著减低,LH脉冲频率无明显改变。LH的平均基础分泌水平和脉冲幅高显著相关。本研究表明,植入E_2抑制垂体LH的分泌,其作用可能主要是抑制LH对GnRH的反应,因此,作用部位是在垂体水平。LH基础分泌水平的下降,亦可能是E_2的抑制作用所致。     

FAILURE OF NALOXONE TO ALTER EXERCISE-INDUCED GROWTH HORMONE AND PROLACTIN RELEASE IN NORMAL MEN

Growth hormone and prolactin levels during standardized exercise tests were measured in ten normal male volunteers, with and without previous intravenous administration of 4 mg naloxone. No significant influence of naloxone on hormone release could be observed. The lack of effect indicates that an opioid pathway is not involved in exercise-induced growth hormone and prolactin release in humans, in contrast to that in rats.     

BROMOCRIPTINE SUPPRESSION OF TRH-STIMULATED PROLACTIN AND THYROTROPHIN RELEASE AND ACCOMPANYING INHIBITION OF BROMOCRIPTINE INDUCED GROWTH HORMONE RELEASE BY TRH IN NORMAL MAN

Six normal fasting males received on four separate occasions in random order (1) a placebo tablet followed 60 min later by 200 microgram of TRH intravenously (2) bromocriptine 2.5 mg orally followed by TRH intravenously (3) bromocriptine 2.5 mg orally followed by a placebo injection and (4) placebo tablet followed by placebo injection. Plasma prolactin and TSH responses to TRH were decreased following bromocriptine pretreatment. The rise of plasma growth hormone after bromocriptine was inhibited by TRH. The rise in plasma FSH seen after TRH injection was not influenced by bromocriptine pretreatment. Circulating LH and insulin concentrations were unaffected by any drug administration. These results suggest a dopaminergic influence on prolactin and TSH release in normal men, an inhibitory effect of TRH on bromocriptine stimulated growth hormone secretion, and no dopaminergic modulation of basal insulin secretion.     

GROWTH HORMONE MODULATION OF ARGININE-INDUCED GLUCAGON RELEASE: STUDIES OF ISOLATED GROWTH HORMONE DEFICIENCY AND ACROMEGALY

Plasma glucagon and insulin responses to l -arginine were compared in normal controls and patients with isolated growth hormone deficiency and acromegaly. Patients with isolated growth hormone deficiency were characterized by high plasma glucagon response and low plasma insulin response, whereas acromegalic patients showed exaggerated plasma glucagon response and almost normal insulin response. These results suggest that growth hormone is probably required for optimum function of the islets, and since hyperglucagonaemia was observed in both growth hormone deficiency and acromegaly, metabolic disturbances stemming from the respective primary diseases may affect glucagon secretion.     

SPONTANEOUS GROWTH HORMONE (GH) PULSATILITY IS THE MAJOR DETERMINANT OF GH RELEASE AFTER THYROTROPHIN-RELEASING HORMONE IN ADOLESCENT DIABETICS

GH release is abnormally regulated in insulin-dependent diabetes (IDDM), and paradoxical stimulation of GH release after TRH has been reported. However, overnight GH pulsatility is increased in IDDM, and it may be difficult to distinguish TRH-stimulated release from spontaneous secretory episodes. To resolve this question, we carried out two overnight GH profiles followed by either TRH or saline control tests in six adolescents with IDDM; ages 11.4-14.7 years, duration IDDM 2.4-6.7 years. A rise in GH was seen in four of six following TRH, but with no consistent pattern. A rise was also seen in four of six following saline. Peak GH levels were similar after TRH and saline (19.3 +/- 4.4 vs 25.8 +/- 5.5 mU/l; mean +/- SEM). Mean blood glucose was no different during TRH and saline tests (9.5 +/- 1.6 vs 7.5 +/- 0.6 mmol/l). The two subjects who had an early GH peak after TRH were those in whom GH levels had already begun to rise, suggesting the coincident occurrence of a spontaneous GH pulse. The timing of the next GH pulse could be predicted equally well after TRH and saline from the overnight secretory profile using autocorrelation. Paradoxical GH stimulation after TRH is not seen in adolescents with IDDM, but apparent responses may be due to timing coincident with the increased spontaneous pulsatility.     

SEX HORMONE LEVELS AND GONADOTROPHIN RELEASE IN THE POLYCYSTIC OVARY SYNDROME

The response to synthetic luteinizing hormone-releasing hormone was studied in eighteen patients with the polycystic ovary syndrome. The release of follicle-stimulating hormone was similar to that found in normal women. The mean response of luteinizing hormone was similar to that found in the luteal phase, but significantly greater (P<0.02) than that found in the early follicular phase of the normal menstrual cycle. Basal serum levels of FSH and LH, estimated in twenty-five patients, were similar to those found in normal subjects. The sex hormone binding globulin capacity was reduced in twenty-four of them. Basal serum testosterone levels were elevated in twelve of twenty-two patients and the mean level was significantly greater (P<0.01) than the mean level of normal women. Basal serum androstenedione levels were elevated in nine of twenty-two patients and the mean level was also significantly greater (P<0.02) than normal. There was a highly significant negative correlation (r=?0.86; P<0.001) between basal testosterone and LH levels. These data suggest that the pituitary gland of patients with the polycystic ovary syndrome contains adequate amounts of LH but that the ovulatory surge of LH which occurs in normal women is inhibited by testosterone acting on either the pituitary or, more probably, on the hypothalamus.     

THE INTERACTION OF GROWTH HORMONE RELEASING HORMONE WITH OTHER HYPOTHALAMIC HORMONES ON THE RELEASE OF ANTERIOR PITUITARY HORMONES

To determine whether the 29 amino-acid fragment of growth hormone releasing hormone (GHRH) can be combined with other hypothalamic releasing hormones in a single test of anterior pituitary reserve, the responses of anterior pituitary hormones to combinations of an i.v. bolus of GHRH(1-29)NH2 or saline with an i.v. bolus of either LH releasing hormone (LHRH) plus TRH, ovine CRH(oCRH) or saline were studied. Each infusion of GHRH(1-29)NH2 resulted in a rapid increment of the plasma GH value. Infusion of GHRH(1-29)NH2 also caused a small and transient rise in plasma PRL, but no change in the integrated PRL response. The combination of GHRH(1-29)NH2 with LHRH plus TRH caused a larger increment of peak and integrated plasma TSH levels than LHRH plus TRH alone. GHRH(1-29)NH2 did not affect the release of other anterior pituitary hormones after infusion with oCRH or LHRH plus TRH. Because of the finding of potentiation of the TSH-releasing activity of LHRH plus TRH by GHRH(1-29)NH2, the study was extended to the investigation of TSH release after infusion of TRH in combination with either GHRH(1-29)NH2 or GHRH(1-40). In this study the combination of TRH with both GHRH preparations also caused a larger increment of the peak and integrated plasma TSH levels than TRH alone. It is concluded that GHRH(1-29)NH2 possesses moderate PRL-releasing activity apart from GH-releasing activity. In addition, GHRH potentiates the TSH-releasing activity of TRH.(ABSTRACT TRUNCATED AT 250 WORDS)     

TISSUE GROWTH HORMONE RELEASE INHIBITING HORMONE-LIKE IMMUNOREACTIVITY IN EXPERIMENTAL HYPOTHYROIDISM AND HYPOPITUITARISM

Hypothyroidism in rats was associated with an increase in immunoreactive GH-RIH in brain, pancreas and gut, although release from the latter may be diminished as portal GH-RIH-like immunoreactivity was lower than control values. Hypophysectomy resulted in a depletion of immunoreactive GH-RIH in the septum and preoptic area of the brain and gastric antrum, but an increase in pancreas; portal venous GH-RIH-like immunoreactivity was not different from control concentrations, possibly reflecting both elevated and lowered immunoreactive GH-RIH in different regions of tissue subserved by the portal vein. Inferior vena caval GH-RIH-like immunoreactivity was always lower than in the portal vein and was not influenced by tissue pertubations in hypothyroidism and hypopituitarism which made regional blood sampling of great important in evaluating tissue changes.