The effect of thyroidectomy on growth hormone regulation in the ovine fetus.

To test the hypothesis that growth hormone gene messenger RNA abundance in the fetus is subject to the same effects of thyroid hormone previously demonstrated in other situations, we evaluated the effect of thyroidectomy on pituitary GH mRNA content at three gestational ages in the ovine fetus. One of each twin pair of fetal lambs underwent thyroidectomy at 90, 100 or 110 days gestation. Fetal pituitaries were collected 25-30 days later. Plasma GH and IGF-I were measured as well as pituitary GH mRNA content. Serum growth hormone in the thyroidectomy group was less than in the control twins (129.8 vs 187.6 micrograms/l, P = 0.0. GH mRNA was likewise decreased in pituitaries of thyroidectomy fetuses compared to controls (1.01 vs 1.80 units, P = 0.0006). Serum IGF-I and body weight were similar in the thyroidectomy and control twins. We conclude that the ovine fetus in the final trimester of gestation exhibits effects of thyroid hormone on serum GH and mRNA abundance similar to those seen in postnatal animals.

Human pancreatic tumor GH-releasing factor.

Within the past year, three similar peptides with specific growth hormone (GH) releasing effects have been extracted from human tissue, identified, and synthesized. Human pancreatic tumor GH releasing factor (I-40)-OH (hpGRF-40) was the sole hpGRF isolated from the pancreatic tumor of a patient in Charlottesville and was the predominant peptide isolated from the pancreatic tumor of a patient in Lyon. The Lyon tumor also contained hpGRF(1-37)-OH and hpGRF(1-44)-NH2. Both immunological and biochemical data suggest that hpGRF-40 and hpGRF-44 are present in the human hypothalamus and may be the human GH releasing hormone(s) (GHRH). In cultures of rat pituitary cells, hpGRF stimulates GH but affects neither basal and dopamine-inhibited prolactin release nor basal and gonadotropin releasing hormone (GnRH)-stimulated luteinizing hormone (LH) release. hpGRF stimulates cyclic AMP production within seconds, an effect which is blocked by somatostatin. In contrast, while hpGRF stimulates phosphatidylinositol turnover in the pituitary, the effect is not inhibited by somatostatin. In the human, hpGRF-40 (1 microgram/kg) given intravenously (i.v.) stimulates GH release within 5 minutes. hpGRF-40 does not elevate serum prolactin levels, thyrotropin (TSH), LH, or corticotropin (measured indirectly through plasma cortisol), or blood glucose or plasma concentrations of insulin, glucagon, pancreatic polypeptide, cholecystokinin, gastrin, gastric inhibitory peptide, motilin, or somatostatin. When graded doses of hpGRF (0.1-10 micrograms/kg) are given i.v., no differences are noted in the maximal levels of serum GH achieved.(ABSTRACT TRUNCATED AT 250 WORDS)

Extrahypothalamic growth-hormone-releasing factor (GRF) secretion is a rare cause of acromegaly: plasma GRF levels in 177 acromegalic patients.

To assess the frequency with which acromegaly is caused by ectopic secretion of GRF, we collected plasma samples from 177 unselected acromegalic patients. The samples together with those of three acromegalic patients with previously diagnosed tumors secreting GRF and of normal subjects were assayed in 3 independent GRF RIAs. Plasma immunoreactive GRF (IR-GRF) levels in normal subjects were either undetectable or detectable at levels up to 62.5 pg/ml. In none of the 177 specimens from acromegalic patients were IR-GRF values detectable in all assays, and in the most sensitive assay, the levels were similar to those in normal subjects, with the highest level measuring 82 pg/ml. In contrast, plasma IR-GRF found in the 3 patients with tumors that secreted GRF ranged from 2.0-24.4 ng/ml. These data suggest that extrahypothalamic GRF secretion is a rare cause of acromegaly. However, it is important that this rare cause of acromegaly be diagnosed before the patient has unnecessary surgery and/or irradiation directed at the pituitary. We recommend that plasma IR-GRF be measured in each new acromegalic patient.

Plasma growth hormone responses to constant infusions of human pancreatic growth hormone releasing factor. Intermittent secretion or response attenuation.

Administration of human pancreatic tumor growth hormone (GH) releasing factor (hpGRF[1-40]) as a single injection to normal human subjects stimulates the secretion of GH in a dose-responsive manner. In the present studies, hpGRF(1-40) was infused in a graded stepwise manner over a 6-h period in order to determine whether the GH secretory response would be sustained. Normal adult males received four consecutive 90-min infusions of hpGRF(1-40) at doses of 1, 3.3, 10, and 33 ng/kg per min, preceded and followed by a 90-min saline infusion; and the plasma GH responses were compared with those during a separate control infusion. Plasma GH levels were significantly elevated by each hpGRF(1-40) infusion; and dose responsiveness was evident for the lowest three doses. Mean integrated GH secretory rates for the four doses were 1.95, 3.29, 4.29, and 3.65 times those of the respective control study. Plasma GH responses exhibited considerable variability, frequently decreasing during the latter part of each infusion; and at the highest dose, they decreased continuously beginning shortly after the onset of infusion. Episodic GH secretion occurred in individual subjects during each of the infusion periods. The possible contribution of hypothalamic somatostatin secretion to the diminished GH responsiveness was evaluated by determining plasma thyroid stimulating hormone (TSH) levels during the infusions and the TSH responses to thyrotropin-releasing hormone (500 micrograms i.v.) during a separate hpGRF(1-40) infusion of 2 ng/kg per min. Neither basal nor stimulated TSH levels differed between GRF-infused and control groups. The results indicate that GH secretion is dose responsive to hpGRF(1-40) infusions, though the response to hpGRF(1-40) infusions, though the response is complex. The absence of impaired TSH secretion provides evidence against a mediating role of somatostatin. The explanation for the loss of GH responsiveness remains undetermined but could include GRF-induced receptor down-regulation, a postreceptor effect, or, in spite of our negative results, a somatostatin-mediated inhibition.

Human pancreatic tumor growth hormone-releasing factor: dose-response relationships in normal man.

Human pancreatic GRF (hpGRF-40; 1 microgram/kg, iv) selectively stimulates GH release in normal men (9). We now report the effects of graded doses of hpGRF-40 on GH release in 12 normal men. Mean peak increments in serum GH after vehicle and the various doses of hpGRF-40 were 1.13, 11.40, 14.60, 17.01, 14.45, and 15.60 ng/ml after vehicle and 0.1, 0.33, 1.0, 3.3, and 10 micrograms/kg hpGRF-40 (iv bolus), respectively. Peak values were observed 30-60 min after hpGRF-40 treatment. There was considerable variability of responsiveness among individual subjects, and no dose-response relationship between the doses and maximal GH values was found. However, the higher doses of 3.3 and 10.0 micrograms/kg resulted in a more prolonged and biphasic pattern of GH release. A side effect of facial flushing of less than 5-min duration occurred in 4 or 6 subjects who received 3.3 micrograms/kg and in all 5 who received 10 micrograms/kg of hpGRF-40. No changes in serum glucose, LH, TSH, PRL, plasma cortisol, or 8 enteropancreatic hormones occurred after hpGRF-40 treatment. There were small increases in serum somatomedin C levels 24 h after the administration of various doses of hpGRF-40 in 11 of 13 studies. Plasma immunoreactive GRF levels measured 5 min after injection were 0.09, 2.0, 4.9, 23.9, and 66.6 ng/ml after 0.1, 0.33, 1.0, 3.3, and 10 micrograms/kg hpGRF-40, respectively. Serum GH responses after insulin-induced hypoglycemia were compared to GH responses after hpGRF-40. Comparable peak GH stimulation occurred with both provocative tests. Mean +/- SEM peak GH was 20.2 +/- 1.0 ng/ml after insulin and 20.9 +/- 3.2 after hpGRF-40 treatment. hpGRF-40 selectively stimulates GH release in normal men over a dose range of 0.1-10 micrograms/kg and is an effective probe to investigate the dynamics of GH release.

Metabolic clearance and plasma disappearance rates of human pancreatic tumor growth hormone releasing factor in man.

The metabolic clearance rate (MCR) and plasma disappearance rate (t1/2) of human pancreatic tumor growth hormone releasing factor [hpGRF(1-40)] was determined in normal adult male subjects by single injection and constant infusion techniques. Single injections of 1, 3.3, and 10 micrograms/kg hpGRF(1-40) were administered intravenously, plasma immunoreactive (IR) GRF levels were measured during the subsequent 180 min, and biexponential curve analysis was performed. Graded, dose-constant infusions of hpGRF(1-40) at rates of 1, 3.3, 10, and 33 ng/kg per min were administered and the MCR was calculated from measurement of steady state plasma IR-GRF levels at each infusion rate. The postinfusion disappearance rate was determined by linear regression analysis of plasma IR-GRF levels during the 120-min period after cessation of the infusion. The calculated MCR during the single injection study was 194 +/- 17.5 liters/m2 per d and was not significantly different from the calculated value during the constant infusion study (202 +/- 16 liters/m2 per d). The disappearance rate during the single injection study was subdivided into two linear phases: an initial equilibration phase (7.6 +/- 1.2 min) and a subsequent elimination phase (51.8 +/- 5.4 min). The latter was similar to the linear disappearance rate observed (41.3 +/- 3.0 min) after cessation of the constant infusion. The chromatographic and biologic characteristics of plasma IR-GRF, 30 min after injection, were similar to those of synthetic hpGRF(1-40). The results have been discussed in relation to the MCR of other hypothalamic hormones and have been used to extrapolate secretion rates of GRF in patients with ectopic GRF production.

Ectopic growth hormone-releasing factor stimulates growth hormone secretion in the urethane-anesthetized rat in vivo.

The in vivo bioactivity of ectopic growth hormone-releasing factor (GHRF) was examined in estrogen-primed, urethane-anesthetized male rats bearing intracarotid catheters. Ectopic GHRF was isolated from a carcinoid tumor metastatic to the liver from a patient with gigantism and elevated plasma growth hormone (GH) levels and was partially purified by reverse phase high performance liquid chromatography for intracarotid injection. Ectopic GHRF elicited a promt rise in plasma GH which peaked at 5 min. The time course of the response resembled that to prostaglandin E1, a known potent direct stimulator of GH secretion in vivo. The effect of ectopic GHRF was dose related in the range of 10-100 U/rat which represents approximately 30x the effective in vitro dose range/10(5) cells in rat adenohypophyseal cell cultures. The in vivo response to ectopic GHRF was completely blocked by the simultaneous intracarotid administration of the GH release inhibitory peptide, somatostatin. These findings lend further support for a role of GHRF from human tumors as a potent physiological stimulator of GH release.

Evidence for lactotroph dopamine resistance in idiopathic hyperprolactinemia.

Previous studies in patients with idiopathic hyperprolactinemia (IH) that have suggested the presence of decreased central dopaminergic tone have assumed normal responsiveness of lactotrophs to dopamine (DA). We have examined DA sensitivity in 17 women with IH and 19 female controls by evaluating the plasma PRL responses to successive infusions of increasing concentrations of DA (4, 40, and 400 ng/kg . min) as well as to a dopaminergic agonist, bromocriptine (2.5 mg, orally), and to a dopaminergic agonist, bromocriptine (2.5 mg, orally), and to a dopaminergic receptor blocker, domperidone (2 mg, iv). PRL levels in controls were unchanged during a saline infusion, but decreased by 34 +/- 7% (mean +/- SE) at the end of the lowest DA infusion (P less than 0.05 vs. saline). Progressive PRL suppression was produced with each increasing dose. In contrast, in patients with IH, the lowest dose produced no significant suppression from basal PRL levels (P less than 0.001 vs. controls); at 40 ng/kg . min DA, fractional suppression was evident but was less than that in controls (P less than 0.01); at 400 ng/kg . min, fractional PRL suppression in IH patients was indistinguishable from that in controls (70 +/- 6% vs. 73 +/- 4%). Patients with IH also exhibited markedly reduced and delayed PRL response to domperidone (P less than 0.02 vs. controls). Significant impairment of the PRL-lowering effect of bromocriptine was observed in the IH patients between 1 and 2 h (P less than 0.02 vs. controls), and their responses to bromocriptine were again delayed. The results indicate the presence of a relative resistance to DA in patients with IH. This resistance is compatible with a decrease in the number or affinity of lactotroph DA receptors.

Ectopic growth hormone releasing factor stimulates growth hormone release from human somatotroph adenomas in vitro.

The effects of an ectopic growth hormone releasing factor (E-GHRF) from a carcinoid tumor were studied in three human GH-secreting pituitary adenomas in monolayer culture. GH release by the adenomas was stimulated by 55 +/- 10%, 57 +/- 8%, and 59 +/- 17% during a 4 h exposure to E-GHRF at concentrations of 3, 0.8, and 24 Units/ml, respectively. Two of the tumors also secreted prolactin (PRL) and in one, E-GHRF (0.8 Units/ml) stimulated PRL release by 48 +/- 8%. GH and PRL release were both suppressed by somatostatin (10(-8)M) in two of the adenomas. These results 1) demonstrate for the first time E-GHRF stimulation of GH release from human pituitary tissue in vitro, 2) support an etiologic role for E-GHRF in the development of acromegaly, and 3) indicate that GH-secreting adenomas retain the capability of responding to GHRF.