Effects of methyldopa on prolactin and growth hormone.

The effects of administration of methyldopa on serum prolactin and growth hormone (GH) concentrations in hypertensive patients were studied. Single doses of methyldopa (750 or 1000 mg) significantly increased serum prolactin levels, peak concentrations occurring four to six hours after drug administrations. Long-term methyldopa treatment was associated with threefold to fourfold increases in basal prolactin levels compared with those in normal subjects. In patients treated with methyldopa for two to three weeks the GH response to insulin hypoglycaemia was significantly greater than in normal subjects and untreated hypertensive patients. In contrast, patients treated for prolonged periods (mean 13-4 months) had a GH reponse indistinguishable from normal.     

Growth hormone response to growth hormone releasing hormone 1-40 in Turner's syndrome

The response of growth hormone (GH) to acute administration of GH-releasing hormone 1-40 (GHRH) was evaluated in 12 patients with Turner's syndrome and in 12 prepubertal or early pubertal girls. In 7 of 12 patients GHRH induced a definite increase (greater than 10 ng/ml) of plasma GH levels. In 5 patients there was a poor GH rise after GHRH administration (less than 10 ng/ml). Overall, the mean GH response of patients was significantly lower than that of normal girls. Five out of 7 patients with a 45 X,O karyotype had a reduced GH rise after GHRH, while all patients with non X,O karyotype (mosaicism and/or 46 X,iX) had a normal GH response to GHRH. Although the cause of short stature in patients with Turner's syndrome is most likely multifactorial, a reduced pituitary GH reserve, as documented by the reduced GH response to GHRH in some of our patients, may contribute to the growth impairment in this disorder.     

Insulin hypoglycemia test and releasing hormone (corticotropin-releasing hormone and growth hormone-releasing hormone) stimulation in patients with pituitary failure of different origin

To investigate the efficacy of endocrine evaluation in diagnosing and localizing the cause of anterior pituitary failure, 17 patients with suprasellar space-occupying lesions, 4 patients with intrasellar tumors, 8 patients with no detectable anatomical lesion, 1 patient with posttraumatic failure and 1 patient with septooptical dysplasia were investigated. Endocrine evaluation consisted of measuring adrenocorticotropic hormone (ACTH), cortisol, and growth hormone (GH) levels during insulin hypoglycemia test (IHT) and after administration of corticotropin-releasing hormone (CRH) and growth hormone-releasing hormone (GRH). In addition, basal prolactin levels, gonadal and thyroid function were evaluated. The results showed that 4 of 17 patients with suprasellar tumors had normal ACTH and GH responses during IHT and after releasing hormone (RH) administration. Five of these patients had a normal ACTH or cortisol rise but no GH response during IHT. All 5 had a normal ACTH and 3 had normal GH rise after RH. Seven patients with suprasellar tumors had no ACTH or GH response during IHT, but all had an ACTH response to CRH. Only 3 of this group had a GH response to GRH. There was one exception of a patient who showed a GH and ACTH rise during IHT but only a blunted ACTH and no GH rise after RH administration. Four patients with pituitary failure and no demonstrable lesion had an ACTH rise after CRH but no GH rise after GRH, whereas in 3 patients with isolated ACTH deficiency no ACTH rise after CRH was seen. In 4 patients with nonsecreting pituitary tumors normal ACTH responses to IHT and CRH were seen, whereas GH rose during IHT only in 1 patient.(ABSTRACT TRUNCATED AT 250 WORDS)     

Responses of growth hormone to metoclopramide in normal women and amenorrheic women with or without hyperprolactinemia

Response of growth hormone (GH) release to metoclopramide (MCP), a dopamine antagonist, was evaluated in normal women, hyperprolactinemic-amenorrheic patients with pituitary microadenoma and normoprolactinemic-amenorrheic patients. Mean basal concentrations of serum GH and prolactin (PRL) in amenorrheic patients were not significantly different from those in normal women except PRL concentrations in hyperprolactinemic patients. Serum GH concentrations significantly increased after MCP administration in normal women and normoprolactinemic-amenorrheic patients, but not in hyperprolactinemic patients. Dopamine causes modest and transient GH secretion in some subjects. Therefore MCP is not likely to stimulate GH secretion through its effect as a dopamine antagonist, and the mechanism of action of MCP on GH secretion is not known. Although the cause of the absence of GH response to MCP in hyperprolactinemic patients is unclear, it may be related to the increased hypothalamic dopaminergic tone which is operative in such patients or it may reflect a direct action of PRL on hypothalamic-pituitary GH regulation.     

Somatomedin, transferrin and amino-acids in serum following injection of human growth hormone in children with growth disease

17 children with growth retardation (12 with idiopathic hypopituitary dwarfism, 2 with craniopharyngioma and 3 constitutionally short) were studied for three days following a single intramuscular injection of human growth hormone. Somatomedin activity was bioassayed using both sulphate incorporation into chick embryo cartilage and thymidine uptake by human lectin-activated lymphocytes. In hypopituitary patients it showed a significant response, maximal 24 hours after the injection, and significantly correlated for the two bioassays. The aminoacid content of the incubation medium used for thymidine bioassay appeared as an important factor: both glutamine and nonessential aminoacids are required to obtain significant stimulation by low serum concentrations, thus increasing the sensitivity of the assay but reducing the differences between normal and hypopituitary sera. Transferrin levels in serum were significantly lower in hypopituitary dwarfs. They did not rise in the three days following hGH. Aminoacid levels were lower in idiopathic GH deficient patients than in other groups, and did not show short term increase in the fasting samples collected after hGH administration.     

Laron-type dwarfism: heterogeneity of the biochemical abnormality in 3 children and their parents

The authors report three cases of Laron-type dwarfism (LTD) having clinical features similar to those of congenital growth hormone (GH) deficiency, but with high levels of plasma GH and a lack of effect of exogenous GH on their growth. The main plasma growth hormone binding protein (GHBP), recently identified and considered as being identical to the extracellular part of the cell receptor to GH, was absent in two of the three patients, and lower than normal in their parents, suggesting a defect of the cell GH receptor. The third patient and his parents had a normal level of GHBP, suggesting a defect limited to the intracellular domain of the receptor or lying beyond the receptor. The conclusion is that there are two different biochemical abnormalities corresponding to LTD.     

Bioassay of growth-stimulating activity of serum: comparison of lymphocyte and cartilage assays in normal and growth hormone-deficient children

The somatomedin and/or growth-stimulating activity of serum from hypopituitary children and short children with normal growth hormone (GH) response to stimulation tests were studied using different bioassays: thymidine incorporation into human activated lymphocytes; sulfate incorporation into chick embryo cartilage; and simultaneous thymidine uptake into the same cartilages. The results showed that lymphocyte assay is highly sensitive to small amounts of serum and is GH-dependent in children with low GH secretion. On the contrary, the cartilage assays need higher serum concentration and their GH-dependence appears only in subjects with normal or low-normal GH secretion. The lack of correlation between the results of the three bioassays suggests that they measure both somatomedins and different serum factors involved in the regulation of growth.     

Plasma growth hormone response to synthetic GH-RH1-44 in 52 children and adults with growth hormone deficiency of various etiologies

52 patients (42 children and 10 adults) with growth hormone deficiency (GHD), grouped into four diagnostic categories, and 6 children with constitutional short stature who served as controls were tested for plasma GH response to synthetic GH-RH1-44 given in an intravenous bolus. The response was classified into three degrees according to the magnitude of the maximal rise: Good, greater than 9 ng/ml; Partial, 3.1-9.0 ng/ml; None, less than or equal to 3 ng/ml. Among the GHD patients the highest response was observed in patients with partial growth hormone deficiency (PGHD), and 60% of the children with isolated GH deficiency (IGHD) showed an increase in plasma GH levels. Nevertheless, the response of the GHD patients was lower than that in the control group. In the children and adolescents with PGHD and IGHD the response was not age related. Among those with multiple pituitary hormone deficiencies-idiopathic (MPHD-ID) there was no response in the adolescents although a hypothalamic disorder had been documented by other tests. Among those with MPHD-organic (MPHD-ORG) the GH-RH stimulated GH secretion in the patients with glioma, who had received only irradiation treatment, and in the youngest of the patients with craniopharyngioma. Of the 10 young adults tested none showed a good response. It is concluded that GH-RH is useful in differentiating between GH deficiency of hypothalamic origin and that of pituitary origin, and in selecting those patients who might benefit from long-term treatment with GH-RH in the future.     

Clonal inheritance of rRNA gene activity: Cytological evidence in human cells

Clone-specific silver staining patterns of the nucleolus organizers (NOs) were observed in clones deriving from a human diploid fibroblast culture. Each specific staining pattern corresponds to one of the nine patterns observed in the general population. Since silver stainability of the NOs is related to rRNA gene function, these data demonstrate the clonal inheritance of rRNA gene activity.     

Plasma growth hormone responses to repetitive administrations of growth hormone releasing factor in patients with pituitary dwarfism

Plasma growth hormone (GH) responses to the repetitive administrations of synthetic human pancreatic growth hormone releasing factor (hpGRF-44) were studied in 15 patients with GH deficiency (11 diagnosed as idiopathic and 4 diagnosed as secondary to hypothalamo-pituitary tumor). hpGRF-44 was administered by single iv bolus (2 micrograms/kg), repetitive im (100 micrograms, twice a day), and/or repetitive iv infusion (2.5 micrograms/min for 90 min, once a day) for three to six consecutive days. Three of the eleven idiopathic GH deficient patients had plasma GH responses to both single iv bolus injection and repetitive administrations by im, or iv infusion of hpGRF. In four of the remaining eight, who had not had peak plasma GH levels above 5 ng/ml to a single iv bolus of the peptide, repetitive administrations of hpGRF-44 by im injection and/or iv infusion induced GH responses to the peptide. In the four patients with secondary GH deficiency, three had plasma GH response to hpGRF administration but one patient, who had indications of pituitary disorder, did not show any plasma GH response to either single iv injection or repetitive administrations of hpGRF-44. These data show that repetitive administrations of hpGRF-44 can induce plasma GH responses in some GH deficient patients who do not respond to a single iv bolus of the peptide.     

Effects of human growth hormone administration on growth rate and growth-stimulating activity of serum, measured by lymphocyte bioassay in hypopituitary children

The acute effect of human growth hormone (hGH) upon the serum bioassayable growth-stimulating activity was compared to the long-term effects of hGH on growth rate in two groups of hypopituitary patients aged 2-18 years. 12 patients had complete GH deficiency with GH peak below 3.5 ng/ml at two stimulation tests. 15 others, having both GH peaks below 8 ng/ml and at least one above 3.5 ng/ml, were considered as having partial GH deficiency. The growth-stimulating activity of serum was measured by its effect at concentrations 0.03 to 1.25% upon thymidine incorporation into lectin-activated normal human lymphocytes, named thymidine activity (TA). In patients with complete GH deficiency, the pre-treatment TA was positively correlated with the peak response of GH to stimulation tests. The increase of TA after 3-4 days of hGH treatment was positively correlated with the pretreatment TA level, and negatively correlated with the peak GH level. The effect of a 6-12 months therapeutic course of hGH upon the growth rate was positively correlated with the acute increase of TA. No such correlations were found in patients with partial GH deficiency. Many works have discussed the relationship of acute somatomedin responses and long-term clinical results of treatment with hGH in GH-deficient children. The present data, using a highly sensitive bioassay of serum stimulating activity, suggest that the degree of GH deficiency is an important factor to be considered. The response of GH-dependent serum growth factors to acute treatment with hGH could have more predictive value in cases with total lack of growth hormone than in cases of partial deficiency.     

Episodic and TRH induced growth hormone release in primary hypothyroidism of man and rat.

In 27 hypothyroid subjects studied over 20 to 120 minutes, the concentration of serum growth hormone (GH) was variable with the amplitude and frequency of the secretory patterns similar to those reported by others for normal individuals. Serum GH, after the administration of thyrotropin releasing hormone (TRH) did not differ from values observed as spontaneous surges, in contrast to a consistent increase in thyrotropin and prolactin. Episodic secretion of GH persisted in thyroidectomized rats and did not differ significantly from that present in intact controls. It is concluded that episodic GH secretion is not abolished in primary hypothyroidism and that TRH is not a constant GH secretagogue in human subjects with hypothyroidism.     

Investigation of human growth hormone releasing factor in adults

A dose-effect relationship between human growth hormone (GH) releasing factor (hGRF) and GH response was demonstrated for doses ranging from 5 micrograms per subject (minimal active dose) to 40-80 micrograms per subject (minimal dose for maximal effect). Bioactivity of GH released under hGRF was proven in the Nb2 lymphoma cell multiplication assay. Unwanted effects were observed for doses equal to or larger than 150 micrograms. Pharmacokinetic parameters were calculated from the immunoreactive GRF plasma concentrations obtained after intravenous injections of various doses. The half-lives were 6.8 +/- 0.4 min and 43.2 +/- 3 min for distribution and elimination phases, respectively. Subcutaneous administration of hGRF was shown to be effective for promoting GH release, with doses higher than those required by intravenous administration. Intermittent intravenous injection of hGRF, at 3-hour intervals, resulted in a decrease in the magnitude of GH response in normal subjects.     

Chronic growth hormone administration does not suppress endogenous growth hormone secretion in patients with neurosecretory growth hormone dysfunction.

Short children who respond normally to growth hormone (GH) stimulation, but have a subnormal spontaneous secretion of GH (neurosecretory GH dysfunction, NSD) are treated with exogenous GH which might suppress their endogenous GH secretion. The effect of chronic administration of GH (8-24 months) on plasma GH responses to GHRH, clonidine and spontaneous GH secretion were studied in 17 NSD patients. The diagnosis of NSD was based on a normal GH response to clonidine (greater than 10 micrograms/l) and an integrated concentration of (IC-GH) GH less than 3.2 micrograms/l. The GH dose used in this study was 0.25 IU/kg three times a week in 10 patients and 0.05 IU/kg daily in 7 patients. Insulin-like growth factor I levels (nmol) increased significantly on therapy from 9.3 +/- 3.8 to 24.4 +/- 22.4 (p less than 0.001). The GH response (microgram/l) to GHRH was 20.4 +/- 5.5 before treatment and 22.4 +/- 6.2 on GH. Peak GH after clonidine was 22.4 +/- 8.9 and 22.8 +/- 8.1, respectively. There was no significant decrease in the number of GH spontaneous peaks (1.8 +/- 0.7 vs. 2.0 +/- 0.7, respectively) or in the area under the curve. A subcutaneous GH bolus of 0.25 IU/kg in 4 patients resulted in a GH peak of 55-82 micrograms/l at 3-5 h and a gradual return to basal levels at 15-20 h after GH administration. The first spontaneous GH peak appeared 26-28 h after GH injection, peak amplitude was 10-15 micrograms/l.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunoreactive growth hormone (GH) secretion by human lymphocytes: augmented release by exogenous GH

Peripheral blood mononuclear cells (PBMCs) from normal adults secreted small amounts of human growth hormone (GH; 0.2-0.6 pg/10(5) cells/7 days culture) as measured by a highly sensitive enzyme immunoassay. Stimulation of PBMCs with phytohemagglutinin (PHA) consistently showed a 4-6 fold increase in GH secretion. Transformed B-lymphocytes by Epstein-Barr virus also secreted GH (0.8-4.8 pg/5 x 10(4) cells/7 days culture). GH secreted by lymphocytes comigrated with pituitary GH on an Ultrogel AcA44 column. Addition of GH during the culture augmented endogenous GH secretion from PHA-stimulated PBMCs. GH-releasing hormone and a somatostatin analogue, SMS 201-995, did not affect GH secretion from non-stimulated and PHA-stimulated PBMCs. These findings suggest that both T and B lymphocytes secrete immunoreactive GH in a different manner from that in the anterior pituitary.     

Growth hormone response to thyrotropin-releasing hormone in acromegalic patients: reproducibility and dose-response study.

The aim of the study was to analyze 14 consecutive patients with active acromegaly who had not undergone any therapy, the dose response of growth hormone (GH) to thyrotropin-releasing hormone (TRH), the existence of reproducibility of such response as well as to rule out the possibility of spontaneous fluctuations of GH which would mimic this response. On several nonconsecutive days, we investigated the GH response to saline serum, 100, 200 (twice) and 400 micrograms of TRH administration. We also studied both basal serum prolactin, serum prolactin after TRH administration and thyrotropin values. Our results show an absence of GH response after saline serum infusion, whereas after TRH doses, 36.3 42.8 and 45.4% positive responses were obtained, respectively. All GH responders were concordant to the different doses administered. The mean of GH concentrations of the different doses at different times did not reach significant differences. The response to the administration of the same dose brought about a significative increase, although it was not identical. It demonstrated a progressive increase of the area under the response curve, as did the means of increments after each TRH administration, albeit without reaching statistical significance. Between the GH-responding and GH-nonresponding groups there were no differences in either basal serum prolactin or serum prolactin and thyroid-stimulating hormone levels after TRH stimulation. The present study clearly shows that TRH elicits serum GH release from GH-secreting pituitary tumors. The response was reproducible in qualitative terms rather than quantitative, and no dose-response relationship was found between the TRH concentrations and the amounts of GH secreted.     

Provocation of a paradoxical growth hormone response to corticotropin-releasing hormone by pretreatment with metoclopramide in patients with acromegaly and normal subjects

Two of 7 patients with acromegaly and one of 7 normal subjects exhibited a paradoxical rise in growth hormone (GH) to human corticotropin-releasing hormone (CRH) when pretreated with metoclopramide, although CRH alone did not induce an increase in GH. In one of these two patients with acromegaly, the GH increase to metoclopramide alone also reached the criteria of a paradoxical response. These two acromegalic patients showed a GH increase to metoclopramide pretreatment before and up to two months after surgery. In another acromegalic patient, whose GH level remained high 5 months after surgery, metoclopramide induced an increase in GH level, while in a patient who had an above-normal GH level 18 months after surgery, the resumption of physiological GH secretion after surgery was evidenced by a postoperative absence of a GH response to metoclopramide. It is suggested from these results that the GH response to metoclopramide and the metoclopramide-provoked GH response to CRH in patients with acromegaly result from the secretion of GH from nonadenomatous cells of the pituitary.     

Repetitive injections of growth hormone releasing hormone (GHRH1-44) to normal volunteers and patients with growth hormone deficiency

The present study was designed to answer the following three questions: Is there any difference between the growth hormone (GH) response to i.v. injections of GHRH 1-44 by a slowly injecting hormone pump or to a s. s. or rapid i. v. injection by syringe? Do nocturnal injections of GHRH 1-44 i. v. elicit different GH levels than during daytime? Can repetitive administration of GHRH 1-44 in patient with GH deficiency induce a physiological GH pattern and thereby normalize the condition resulting from a hypothalamic defect? A rapid i. v. bolus injection of 50 micrograms GHRH 1-44 by syringe with an injection time of one second elicited in the same subject at the same time of the day a twofold greater response than a slowly injecting (60 seconds) hormone pump. In six male adult volunteers each GHRH i. v. bolus was followed by a GH secretory pulse. The GH response at night (area under the curve and peak plasma GH levels) was significantly greater than at daytime (P less than 0.05) and greater than the GH pulses measured during a spontaneous nocturnal profile (P less than 0.05). Out of six GH deficient young adult patients who had been receiving extractive GH until two years prior to the study, three responded much like the controls, the other three patients-those who lacked any spontaneous nocturnal GH peaks-had markedly lower GH levels after GHRH (P less than 0.05). However, there was a clear-cut GH release after GHRH injection in each patient.(ABSTRACT TRUNCATED AT 250 WORDS)