Increased Serum Growth Hormone Research Articles

Thyrotropin-releasing hormone in critical illness

The aim of this study was to examine the effect of dopamine infusion on the thyrotropin (TSH), thyroid hormone, prolactin, and growth hormone responses to thyrotropin-releasing hormone (TRH) in critically ill patients. Prospective, randomized, controlled, open-labeled clinical study. The intensive care unit, University Hospital Gasthuisberg, Leuven, over a 1-month period. In 15 critically ill patients receiving dopamine treatment (5 micrograms/kg/min) for a mean of 43.3 +/- 1.2 (SEM) hrs after trauma or cardiac surgery, we studied the TSH, thyroid hormone, prolactin, and growth hormone responses to the administration of two consecutive intravenous TRH boluses of 200 micrograms, with a 6-hr interval. The dopamine infusion was continued in the control group and discontinued in the study group. Serum concentrations of TSH, prolactin, and growth hormone were measured before and 20, 40, 60, and 120 mins after TRH administration. Serum concentrations of thyroxine (T4), triiodothyronine (T3), reverse T3, and thyroid hormone binding globulin were determined before and 120 mins after each TRH injection. There was a > 100-fold interindividual variation in the baseline TSH concentration and in the TSH peak value after TRH administration. Two consecutive doses of TRH evoked a mean 16% increase in serum T4 concentration (p = .003) and a mean 47% increase in T3 (p = .001), whereas serum reverse T3 and thyroid hormone binding globulin values remain unaltered. Each of the TRH boluses increased serum growth hormone concentrations in the continued dopamine and discontinued dopamine groups, by a median of 60% (p = .001) and 68% (p = .001), respectively. Three hours after dopamine withdrawal, there was a three-fold increase of the peak TSH response (p = .001), a higher T3 response (p = .01), and a ten-fold increase of the peak prolactin value (p = .001) in response to TRH administration. The TSH response to TRH administration in critical illness presents a striking interindividual variation and dopamine dependent. Repeated TRH administration results in a repetitive increase of TSH, prolactin, growth hormone, T4, and T3, without increasing reverse T3. These observations point toward a potential for TRH as a strategy for reversing the euthyroid sick syndrome, growth hormone deficiency, and immune dysfunction associated with critical illness.

Upregulation of GH receptor and GH binding protein during pregnancy in the GH deficient rat

During pregnancy there are dramatic changes in the endocrine and metabolic status of the mother: growth hormone (GH) is an important regulator of growth and development. A proportion of GH is bound by specific GH binding proteins (GHBP) that closely resemble the GH receptor (GHR). In the rodent both GHBP and the GHR are considered to be GH dependent, and consequently during pregnancy the increase in serum GH is associated with an increase in GHBP. To examine whether an increase in maternal GH is obligatory for elevation of maternal GHBP or GHR during pregnancy, we used a unique GH-deficient (GHD) strain of rats, to avoid the methodological complications of hypophysectomy and assessed serum GH, GHBP and hepatic GHR binding during the course of pregnancy. In GH normal rats, serum GH concentrations increased twofold and GHBP levels increased threefold; there was no change in hepatic GHR binding. In GHD rats, serum GH concentrations were low and did not increase during pregnancy. Nonetheless, levels of both serum GHBP and hepatic GHR binding increased to that measured in normal rats. Thus, an increase in maternal GH concentration is not required for the gestational upregulation of maternal GHBP or hepatic GHR binding, suggesting that other hormones may be essential in modulating the GH axis during pregnancy.

Role of galanin in the regulation of somatotrope and gonadotrope function in young ovulatory women

The aim of the study was to elucidate the role of the neuropeptide galanin in the regulation of somatotropic and gonadotropic function in normal women. Thirteen normally ovulating (aged 28 to 40 years), non-obese (body mass index, 18.4 to 27.1 kg/m 2) women with infertility due to a tubal or male factor were studied. Each woman underwent three tests: (1) bolus intravenous (IV) injection of growth hormone (GH)-releasing hormone (GHRH) (1–29)NH 2 1 μg/kg plus gonadotropin-releasing hormone (GnRH) 100 μg at time 0; (2) IV infusion of porcine galanin 500 μg in 100 mL saline from −10 minutes; and (3) bolus IV injection of GHRH(1–29)NH 2 1 μg/kg plus GnRH 100 μg at time 0 plus IV infusion of porcine galanin 500 μg in 100 mL saline from −10 to +30 minutes. All results are expressed as the mean ± SEM. GH peak after GHRH was 14 ± 5 μg/L; porcine galanin significantly increased serum GH (GH peak, 7.3 ± 1.2) with respect to baseline levels. No significant differences were observed between either GH peak or GH absolute values after galanin as compared with GHRH alone. Porcine galanin significantly enhanced GH response to GHRH (peak, 31.4 ± 4.4μg/L) with respect to either GHRH or galanin alone. Luteinizing hormone (LH)/folliclestimulating hormone (FSH) peaks after GnRH were 16.5 ± 5.3 and 17.4 ± 4 IU/L, respectively. Porcine galanin did not cause significant increases in serum LH and FSH levels with respect to baseline. Galanin coadministration slightly increased LH (peak, 25 ± 6.9 IU/L) but not FSH (peak, 17.1 ± 3.2) maximal responses to GnRH. In conclusion, galanin plays a significant role in the regulation of GH secretion in women, as well as in men. Moreover, this report suggests a minor role of galanin in the regulation of the hypothalamic-pituitary-ovarian axis in women.

Galanin counteracts the inhibitory effects of glucocorticoids on growth hormone secretion in the rat.

The aim of our study was to investigate the effect of galanin on baseline and growth hormone (GH)-releasing hormone (GHRH)-stimulated GH concentrations in conscious, freely moving rats receiving long-term glucocorticoid treatment. Animals were treated for 7 days with an intraperitoneal injection of either vehicle or dexamethasone ([dex] 40 micrograms/d). Rats underwent the following experimental trials: at -15 minutes animals received an intravenous injection of saline or galanin (12.5 micrograms/kg), and at 0 minutes rats received a second intravenous injection of saline or rat GHRH (500 ng/kg). Blood samples were drawn every 5 minutes from -15 to +15 minutes and then at 30 minutes. The GH response to saline + GHRH alone was significantly higher (P < .05) in chronically vehicle-treated rats as compared with chronically dex-treated ones. In contrast, galanin + saline increased serum GH levels in a similar fashion in both chronically vehicle- and dex-treated rats. The response to galanin + GHRH was similar to galanin + saline in chronically vehicle-treated rats, but was significantly enhanced in chronically dex-treated rats. These results suggest that galanin-mediated GH release in rats may involve somatostatinergic pathways.

Bombesin acts to suppress feeding behavior and alter serum growth hormone in goldfish

The acute effects of a single injection of bombesin (BBS) on feeding behavior and serum growth hormone (GH) levels in goldfish were examined. When injected intraperitoneally (IP), BBS (0.5–100 ng/g) caused a dose-dependent decrease in food intake within 30 and 45 min of administration; maximal suppression was achieved at 50 ng/g BBS and was accompanied by an elevation in serum GH levels. Associated with IP injection of BBS was a pronounced spitting out behavior in which food pellets were taken into the oral cavity but immediately expelled. When injected into goldfish deprived of food for 72 h, 50 ng/g BBS was still potent in suppressing feeding behavior and increasing serum GH. Additionally, IP injection of BBS (10 or 100 ng/g) into groups of fish caused a significant increase in circulating serum GH levels at 1.5 h postinjection. Finally, when injected into the third brain ventricle (ICV), 60 ng/g BBS also caused a suppression in food intake and a concomitant increase in serum GH. Groups of fish injected ICV with 5 or 50 ng/g BBS also exhibited a graded increase in serum GH levels at 45 min postinjection. Overall, these data are the first to demonstrate in any lower vertebrate that a neuropeptide acts to suppress food intake and cause concomitant alterations in circulating serum GH levels, following either peripheral or central administration.

2-Adrenergic Receptor-Mediated Regulation of Growth Hormone Secretion in Meal-Fed Holstein Steers

Effects of activation or blockade of alpha 2-adrenergic receptors on serum growth hormone concentrations were studied in Holstein steers (115 +/- 4 days of age; 112 +/- 4 kg body wt). A pelleted diet was available ad libitum for 2 hr each day. Serum growth hormone concentrations were greater for 80 min immediately before feeding compared with 80 min immediately after removal of feed. Relative to saline-injected controls, activation of alpha 2-adrenergic receptors with clonidine (2 micrograms/kg body wt iv) before feeding rapidly increased serum growth hormone concentrations, but clonidine had no effect when administered after feeding. Compared with vehicle-injected controls, blockade of alpha 2-adrenergic receptors with either idazoxan (20 mg/kg body wt sc) or yohimbine (5 mg/kg body wt sc) decreased serum growth hormone concentrations before as well as after feeding. Feeding abolished the stimulatory alpha 2-adrenergic receptor-mediated increase in growth hormone secretion. Our data support the hypothesis that alpha 2-adrenergic receptor stimulation is an essential event mediating pulsatility of growth hormone secretion before feeding and is required to maintain basal concentrations after feeding.

Pituitary-gonadal response to gonadotropin-releasing hormone stimulation is enhanced in men after strenuous physical exercise.

The effects of strenuous physical exercise were studied on the pituitary-testicular response to gonadotropin-releasing hormone (GnRH) stimulation and on growth hormone (GH) and cortisol secretion. Eight healthy adult males were injected twice intravenously with 0.1 mg of GnRH at intervals of 21 days. At the time of the first injection (exercise trial) the subjects had been bicycling for 4 h on the road, and at the time of the second injection (rest trial) they had been resting in a sitting position for 4 h. Blood samples were taken before and after the 4-h period and 30, 60 and 120 min after the GnRH injection. Both testosterone and luteinizing hormone (LH) decreased during the exercise by 18% (p = 0.037) and 29% (p = 0.0028), respectively, but increased after the GnRH injection by 1.4- and 12.9-fold (p = 0.0001 for both). The areas under the testosterone and LH response curves after GnRH were significantly larger in the exercise trial than in the rest trial, threefold (p = 0.013) and 1.3-fold (p = 0.0007), respectively. Growth hormone and cortisol increased during the exercise trial. In the rest trial, the GnRH injection increased serum GH concentrations (p = 0.027). In conclusion, the diminished hypothalamic GnRH secretion seems to be the major cause of the post-exercise decrease in LH and testosterone, but altered sensitivity of the pituitary to GnRH also may be involved. Apparently, the build-up of pituitary LH stores during exercise explains the enhanced LH and testosterone response to GnRH challenge after exercise in comparison to control GnRH challenge.

Actions of Goldfish Neuropeptide Y on the Secretion of Growth Hormone and Gonadotropin-II in Female Goldfish

Neuropeptide Y (NPY) has been recently characterized in the goldfish and the sequence deduced from goldfish brain cDNA clones reveals that goldfish NPY (gNPY) has over 86% identity with human NPY (hNPY) (Blomqvist et al., 1992, Proc. Natl. Acad. Sci. USA 89, 2350-2354). In the present study, we used synthetic gNPY to investigate the role of NPY in the regulation of growth hormone (GH) and gonadotropin-II (GtH-II) in the goldfish. The dose-response relationships of gNPY on GH and GtH-II release were first tested using an in vitro perifusion system for pituitary fragments. It was found that gNPY stimulated both GH and GtH-II release in a dose-dependent manner, with ED 50 values of 1.89 ± 0.9 n M for GH and 4.19 ± 2.9 n M for GtH-II. In addition, the C-terminal fragment gNPY (18-36) stimulated the release of both GH and GtH-II, but with lower potency than did the intact molecule. These results confirm our previous findings using hNPY. The interactions of gNPY and other GH and GtH-II regulators were also examined in the present studies. Prolonged infusion of sGnRH induced initial peak releases of GH and GtH-II, followed by a second phase of sustained hormone release at a reduced level. Application of a 5-min pulse of gNPY during the second phase of sGnRH action further stimulated GH and GtH-II release, but only to the levels similar to those induced by gNPY alone. Prolonged infusion with gNPY induced a rapid desensitization of GH and GtH-II release; the hormone levels returned to basal within 25 min in the continued presence of gNPY. Administration of 5-min pulse of sGnRH during the desensitization phase of continuous gNPY perifusion induced a similar GH response to that induced by sGnRH alone, whereas the GtH-II responses to sGnRH given during gNPY infusion were smaller than the responses to sGnRH alone, suggesting that the mechanisms of gNPY stimulation on GH and GtH-II release may be somewhat different. The gNPY-induced GH release was blocked by somatostatin, a known GH inhibitor; the gNPY-induced GtH-II release was reduced by dopamine, a known inhibitor for GtH-II. Finally, intraperitoneal injection of gNPY induced time- and dose-dependent increases in serum GH and GtH-II levels. Together, these results suggest that NPY may play a physiological role in the regulation of GH and GtH-II secretion in the goldfish.

Interaction between the α2-adrenergic system and nursing in the regulation of growth hormone secretion in the neonatal rat

Separation of neonatal rats from their mothers decreases, while a subsequent period of suckling (nursing) increases, serum growth hormone (GH) levels in neonatal rats. Milk-borne (humoral) factors and neural factors inherent in mother-offspring interaction have been implicated in these phenomena. Conflicting reports have demonstrated the alpha 2-adrenergic agonist clonidine to increase and to decrease serum GH levels in 10-day-old rats. The present experiments were aimed at testing whether an interaction between the alpha 2-adrenergic system and the nursing-induced changes in GH secretion could account for the discrepancy. Rat pups were treated with clonidine (150 micrograms/kg) or the alpha 2-adrenergic antagonist yohimbine (10 mg/kg), and the drug treatment was combined with separation of the mothers and nursing. Yohimbine did not affect serum GH levels in separated two-day-old pups (i.e. basal levels of the hormone), but prevented the nursing-induced increase in serum GH concentration. In two-day-old pups, clonidine had no effect on basal GH levels but, like yohimbine, prevented the increase in serum GH normally associated with nursing. Both yohimbine and clonidine prevented active sucking behavior, i.e. the pups did not search for and/or attach to the nipples of their mothers. Moreover, the pups treated with yohimbine and clonidine were cooler to the touch than the littermate controls. In eight-day-old pups, yohimbine prevented the nursing-induced increase in serum GH and decreased GH levels below the saline-injected, separated control.(ABSTRACT TRUNCATED AT 250 WORDS)

Thyrotropin‐Releasing Hormone Mediates Growth Hormone Release Induced by Milk and Nursing in Neonatal Rats

Previous evidence from this laboratory suggested that growth hormone (GH) release induced by milk in vitro and by nursing in vivo from neonatal rat pituitary glands is mediated by an alternative GH-releasing factor(s) (GRF) distinct from GH-releasing hormone (GHRH(1-43) ). In the present experiments we tested whether thyrotropin-releasing hormone (TRH) could fulfil the criteria of this alternative GRF in neonatal rats. The water-soluble fraction of rat milk (infranatant, prepared by ultracentrifugation) and its methanol/acetic acid extract (milk-borne peptides) stimulated GH release from perifused pituitary glands obtained from 2-day-old rats. Dialysis of the infranatant (mol wt cut-off: 2,000) against 500 volumes of culture medium at 4°C eliminated its GH-releasing activity in the perifusion system, while the infranatant retained its full GRF-like activity when incubated at 4°C without dialysis. The milk-borne GRF eluted as a single peak and coeluted with TRH in a combined gel permeation chromatography (Sephadex G-10) and perifusion set-up. Prolactin secretion was also stimulated simultaneously with the release of GH induced either by milk or by TRH. In a stepwise C(18) reversed-phase chromatography, milk-borne GRF was highly hydrophilic and coeluted with synthetic TRH. The in vitro GH-releasing bioactivities of synthetic TRH and a milk extract purified in C(18) reversed-phase chromatography were abolished by proline-specific endopeptidase. Thus, TRH and milk-borne GRF displayed similar molecular weights, hydropathic characteristics and proteolytic enzyme resistance. In vivo, nursing (which has been reported as a potent stimulus of GH secretion even in the absence of milk-intake) increased serum GH levels in 2-day-old pups. A supramaximal dose of TRH (10 ng/g intraperitoneally) stimulated GH release in 2-day-old pups separated from their mothers for 6 h to a similar extent as nursing. Nursing-induced levels of serum GH were not further elevated by TRH. This failure of TRH to further increase serum GH levels was not due to a maximal GH output by the neonatal pituitary gland, since the GH release induced by the serotonin precursor 5-hydroxy-L-tryptophan was augmented either by TRH or by nursing. These data provide evidence that the milk-borne GRF-like activity in vitro is indistinguishable from TRH, and suggest that TRH (probably of hypothalamic origin) might be the mediator of the nursing-induced release of GH in vivo as a physiological GRF in neonatal rats.

Increased serum growth hormone concentration in feline hypertrophic cardiomyopathy.

Serum growth hormone concentration was measured by radioimmunoassay in 31 cats with hypertrophic cardiomyopathy, 38 normal cats, and 35 cats with other cardiac disease. Cats with hypertrophic cardiomyopathy had a significantly increased serum growth hormone concentration when compared with normal cats and cats with other cardiac disease. The serum growth hormone concentration in cats with hypertrophic cardiomyopathy was less than that previously reported in cats with growth hormone secreting pituitary tumors. Pituitary tumors were not identified in eight of the cats with hypertrophic cardiomyopathy examined at necropsy. An increased serum growth hormone concentration may be measured in cats with hypertrophic cardiomyopathy but it is unclear if the increased serum growth hormone concentration is a cause or effect of hypertrophic cardiomyopathy.

Regulation of Basal and Nursing‐Induced Secretion of Growth Hormone in the Neonatal Rat: The Involvement of Serotonergic, Muscarinic Cholinergic, Alpha2‐Adrenergic, Somatostatin and Growth Hormone‐Releasing Hormone Systems

Abstract Various neural factors are involved in the suckling-induced increase in serum growth hormone (GH) levels in neonatal rats, and, in the present study the serotonergic, cholinergic, somatostatin and GH-releasing hormone (GHRH) systems were investigated. The serotonin (5-HT) precursor 5-hydroxy-L-tryptophan (5-HTP) and the 5-HT receptor agonist quipazine maleate stimulated serum GH levels in 2-day-old rat pups separated from their mothers for 6 h. The increase in serum GH during suckling was further elevated by 5-HTP. The 5-HT antagonist cyproheptadine decreased serum GH levels in separated 2-day-old pups, and although it reduced the amplitude of the suckling-induced increase in serum GH concentration, it did not alter the increase in serum GH on a percentage basis. The effect of the cholinergic muscarinic antagonist atropine sulfate (ATR) was similar to that of cyproheptadine. Moreover, in separated pups, ATR prevented the increase in serum GH induced by 5-HTP. In contrast with 2-day-old pups, ATR completely eliminated the suckling-induced release of GH in 10-day-old rats. However, ATR failed to prevent GH release induced by the alpha(2)-adrenergic agonist clonidine HCI in 10-day-old male pups. While thyrotropin-releasing hormone increased serum GH levels, rat GHRH failed to alter serum GH levels either in separated or in suckled 2-day-old rat pups. Immunoneutralization for rat GHRH eliminated the increase in serum GH induced by clonidine HCI in 10-day-old pups, but (on a percentage basis) failed to prevent the GH-increasing effect of suckling in 2-day-old pups. While somatostatin failed to significantly decrease serum GH in separated 2-day-old pups, it effectively decreased serum GH levels in 2-day-old pups which were suckled. Cysteamine, which depletes hypothalamic somatostatin, increased serum GH in separated 2-day-old pups, and further increased the suckling-induced levels of serum GH. Cysteamine partially prevented the GH-decreasing effect of ATR. The present findings suggest that 1) the serotonergic and cholinergic systems are involved in the regulation of GH secretion as early as day 2 postpartum; 2) the serotonergic and cholinergic systems modulate the basal, and do not modulate the suckling-induced levels of serum GH; 3) the serotonergic system may exert its stimulatory influence on GH secretion only in the presence of a functional muscarinic cholinergic system; 4) the cholinergic system, at least in part, stimulates GH secretion via a cysteamine-sensitive system (probably by inhibiting somatostatin); 5) the cholinergic system is not functionally coupled with the alpha(2)-adrenergic system, which stimulates GH secretion via rat GHRH; 6) since in 10-day-old pups clonidine HCI was effective only in males, while suckling was effective in both sexes, the alpha(2)-adrenergic system is not involved in the suckling-induced increase of serum GH; and finally 7) neither somatostatin nor rat GHRH seem to be involved in the suckling-induced changes in serum GH. The findings are consistent with the hypothesis that the high circulating GH levels in the neonatal rat are due to alternative GH-releasing factors, perhaps thyrotropin-releasing hormone or gamma-aminobutyric acid. The neurohumoral mediator of the suckling-induced GH release in neonatal rats remains to be identified.

Estrogen Action on Growth Hormone in Pituitary Cell Cultures from Adult and Juvenile Macaques*

Basal growth hormone (GH) levels are higher in female than male primates, and estradiol (E) treatment of gonadectomized primates increases serum GH. To determine if the effect of E is mediated at the level of the somatotroph, we verified the effect of E-treatment on serum GH in spayed macaques, and then examined the effect of E on GH secretion in serum-free monkey pituitary cultures. Daily blood samples were obtained from cynomolgus macaques which were spayed upon detection of menstruation and immediately implanted with either empty (n = 5) or E-filled (n = 5) 2-cm silastic capsules. The average level of GH was significantly higher (P less than 0.003) in the E-treated group than in the control group (6.4 +/- 0.7 vs. 3.7 +/- 0.6 ng/ml). Pituitaries from rhesus monkeys were dispersed and cultured in 48-well plates on extracellular matrix in DME/F12 with insulin, transferrin, selenium. Using pituitary cells from a long-term spayed female, two plates were established with and without phenol red. Each plate was treated with E in a dose-related manner (0.001-10 nM) from days 0-18 (4 wells per dose). There was a significant dose-related increase in medium prolactin (PRL) in both plates, but E had no effect on GH. Therefore, the effect of E on GH in spayed monkeys cannot be accounted for by a direct action on somatotrophs. Additional phenol red-free pituitary cultures were established from four juvenile males, one adult male, two juvenile females, and two adult females and treated with E in a dose-related fashion for 28 days. Neither the adult male, the adult female, nor the juvenile female cultures exhibited an increase in GH with E treatment. Only the four juvenile male pituitary cultures showed a variable increase in GH with maximal responses ranging from 5 to 40% over control. This data suggested that the juvenile male pituitary contained an E-sensitive GH-secreting cell population which is not present in the other pituitary cultures. PRL and GH double-immunocytochemical staining of pituitary cultures from an adult female and a juvenile male revealed a significant population of rounded and possibly double-labeled cells in the juvenile male culture which were infrequently seen in the adult female culture. Speculatively, this population could represent mammosomatotroph stem cells that corelease GH and PRL upon stimulation.

Regulatory effects of growth hormone, ghicocorticoids, and thyroid hormone on the estrogen receptor level in the rat liver

The multihormonal regulation of the estrogen receptor in the liver of female rats was studied under in vivo conditions. The steroid receptor level was assayed by hormone binding and specific mRNA analyzed by solution hybridization using a 35S-labeled RNA probe complementary to the ligand-binding domain of the estrogen receptor gene. Serum growth hormone levels were measured and correlated to the effects of glucocorticoid and thyroid hormone administration on the estrogen receptor expression. In animals subjected to adrenalectomy plus thyroidectomy, the estrogen receptor concentration was reduced from 59 fmol/mg cytosol protein to 10 fmol/mg protein (i.e., with 87% relative to control animals). Adrenalectomy or thyroidectomy alone caused a decrease with 14% and 66%, respectively. Substitution with 10 μg betamethasone and 1 μg triiodothyronine daily for 9 days completely restored the receptor content to control levels. Substitution with either hormone alone increased, but only partially restored receptor levels. The effect of betamethasone alone was dose dependent from 10 μg/ d to 100 μg/d. This dose dependence was not seen when the animal simultaneously received 1 νmg of triiodothyronine. Superphysiologic doses of triiodothyronine did not raise estrogen receptor levels above those seen in animals treated with physiologic doses. High doses of triiodothyronine (>20 μg/d) decreased serum growth hormone levels. The estrogen receptor mRNA levels in livers from hypophysectomized animals were increased after treatment with growth hormone (2.5-fold), thyroid hormone (two-fold), and glucocorticoids (1.5-fold). The results obtained indicate a very complex regulation of liver estrogen receptor. Growth hormone plays a central role in this process, and other hormones that influence the serum level of growth hormone also indirectly affect the expression of the estrogen receptor gene. The effect of betamethasone is probably mediated by increased serum growth hormone levels. Furthermore, strong evidence is shown for a direct effect of thyroid hormone on the expression of the estrogen receptor gene in the liver and a possible permissive effect of this hormone for the action of glucocorticoids .

Testosterone and Oxandrolone, a Nonaromatizable Androgen, Specifically Amplify the Mass and Rate of Growth Hormone (GH) Secreted per Burst without Altering GH Secretory Burst Duration or Frequency or the GH Half-Life*

We investigated the mechanisms by which androgens increase mean circulating GH concentrations in boys. We tested two hypotheses: 1) testosterone increases serum GH concentrations at least in part via an androgen receptor-mediated mechanism, rather than exclusively by way of aromatization to estrogen; 2) androgen augments one or more specific features to GH secretion (secretory burst number, amplitude, and/or duration) and/or prolongs the half-life of GH removal. To examine these hypotheses, prepubertal boys with constitutionally delayed development and/or growth were given injections of testosterone (100 mg monthly; n = 7) or treated with oral oxandrolone, a nonaromatizable androgen (1.25 mg twice daily; n = 5). Pulsatile GH release was studied before and during androgen administration by sampling blood at 20-min intervals for 24 h. The immunoreactive GH time series were subjected to a novel deconvolution technique, which revealed that 1) testosterone and oxandrolone each increased mean (24-h) serum GH concentrations significantly; 2) both androgens augmented the daily endogenous GH secretory rate significantly; 3) increased GH production resulted from a higher mass of GH secreted per burst and a higher maximal rate of GH secretion within each burst; and 4) androgens amplified the magnitude of the nyctohemeral rhythm in the mass (but not frequency) of GH secretory pulses. The observed effects of androgen were specific, since the number and duration of GH secretory bursts and the subject-specific GH half-life were unaltered by androgen treatment. We conclude that androgen acting apart from conversion to estrogen is capable of specifically activating the somatotropic axis via distinct neuroendocrine secretory mechanisms.

Effect of Thyrotropin-Releasing Hormone, Triiodothyronine, and Chicken Growth Hormone on Plasma Concentrations of Thyroxine, Triiodothyronine, Growth Hormone, and Growth of Lymphoid Organs and Leukocyte Populations in Immature Male Chickens

One-day-old White Leghorn male chicks were fed different levels of Thyrotropin Releasing Hormone (TRH) (1 and 5 ppm) or Triiodothyronine (T3) (.1 and 1 ppm) for an 8-wk period. In a second experiment, chicken growth hormone (cGH) (10 μg/kg of BW) was injected (iv) into different birds daily for 7 days starting at 7 wk of age. Different groups of birds received both T3 (.1 and 1 ppm) and cGH. Serum concentrations of thyroxine (T4), T3, and growth hormone (GH), lymphoid organ weights, total circulating white blood cells (WBC), and differential counts were measured following hormone treatments.It was found that T3, cGH, or a combination of both significantly lowered serum T4 concentrations. Triiodothyronine supplementation at 1 ppm, alone or with cGH significantly increased serum T3 concentrations. Chicken GH with T3 (.1 ppm) significantly increased serum GH concentrations. Thyrotropin releasing hormone supplementation did not affect serum concentrations of either T4, T3, or cGH. Relative bursa weights were greater in chicks mat received T3 (1 ppm) or TRH (1 or 5 ppm) but not cGH. Relative spleen weights were enhanced in response to cGH alone or with T3 (1 ppm) but not TRH. Total WBC count was significantly increased in response to T3 (1 ppm). Supplementation of T3 (.1 or 1 ppm), TRH (1 ppm), and the combination of cGH and T3 (1 ppm) significantly increased the percentage of lymphocyte cell population. These results demonstrate the impact of feeding hormones on T3, T4, and cGH concentrations in the serum and suggest the involvement of the above hormones in the growth of lymphoid organs as well as the production of lymphocytes.

Sexual Differentiation of Growth Hormone Feedback Effects on Hypothalamic Growth Hormone-Releasing Hormone and Somatostatin

To investigate possible sex differences in the feedback regulation of growth hormone (GH) secretion, concentrations of immunoreactive GH-releasing hormone (GRF) and somatostatin (SS) were measured in the median eminence (ME) and the hypothalamus of male and female rats bearing the MtTW15 tumor, which secretes high amounts of GH and prolactin (PRL). Four weeks after tumor implantation in male rats, the GRF concentration in the whole hypothalamus, including the ME, was decreased by 37% (0.29 +/- 0.02 vs. 0.46 +/- 0.02 ng/mg protein in intact male controls; p less than 0.001) and the concentration of SS was increased by 40% (11.5 +/- 0.7 vs. 8.1 +/- 0.3 ng/mg protein in male controls; p less than 0.01). In female rats, the presence of tumor for 4 weeks caused a smaller (18%) reduction in GRF concentrations (0.27 +/- 0.02 vs. 0.33 +/- 0.03 ng/mg protein in intact female controls; p less than 0.05) and no significant change in SS concentrations (10.2 +/- 0.08 vs. 9.7 +/- 0.8 ng/mg protein in female controls). Tumor-related changes in GRF and SS concentrations were also more pronounced in male rats than in females, when determined separately in the microdissected ME and in the remaining hypothalamus. These differences occurred despite similar increases in serum GH, PRL and insulin-like growth factor I concentrations in male and female tumor-bearing rats. To assess which hormone (GH or PRL) was responsible for these changes, intact male rats were treated for 10 days with 2 daily s.c. injections of rat GH (rGH; 100 and 250 micrograms/day), rat PRL (100 and 250 micrograms/day) or vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of dose and frequency of administration of a potent analog of human growth hormone-releasing factor on hormone secretion and growth in pigs.

Ninety-six pigs (49.5 +/- .5 kg BW) were allotted to six treatments and were injected once (SID) or three times daily (TID) s.c. with a [desamino-Tyr1, D-Ala2, Ala15] human growth hormone-releasing factor (1-29) NH2 analog (GRF-AN). Treatments were T1, noninjected control; T2, saline-injected control (TID); T3, GRF-AN (1.66 micrograms/kg BW, TID); T4, GRF-AN (3.33 micrograms/kg BW, TID); T5, GRF-AN (6.66 micrograms/kg BW, TID) and T6, GRF-AN (10 micrograms/kg BW, SID). Feed protein levels were 14% for T1 and 18.8% for T2 through T6. The GRF-AN increased serum growth hormone (GH) concentration for the entire growing period (about 56 d) in a dose-related manner and did not induce desensitization of the somatotroph cells; in fact, an increase (P less than .05) in the GH response to GRF-AN was observed in T4 and T5 after 1 mo of treatment. This GRF-AN produced (P less than .05) a dose-dependent effect on several variables in animals grown to 110 kg BW: in comparison to T2, T5 increased meat in carcass (6%), carcass length (3%), loin eye area (13%), liver weight (19%), kidney weight (30%), improved feed efficiency (20%) and decreased total feed intake by 50 kg (26%). Compared to T2, average daily gain was increased (P less than .05) by 13% by the 3.33 micrograms/kg TID dose. Blood parameters were measured on d 1, 29 and 57. Increased serum glucose and insulin levels were observed. Triiodothyronine and thyroxine concentrations were increased and decreased, respectively after 28 d of treatment but were unchanged on d 57. This potent GRF analog maintained high GH concentration for at least 56 d and affected several growth parameters and carcass characteristics in a dose-related manner similar in magnitude to that reported in studies using porcine GH.

Relationship between serum growth hormone levels and the brain and pituitary content of immunoreactive somatostatin in the goldfish, Carassius auratus L

In this study, the relationships between endogenous brain and pituitary immunoreactive somatostatin (irSRIF) and circulating growth hormone (GH) levels in the goldfish were examined using two approaches. First, the amount of irSRIF in extracts of the pituitary gland and various brain regions was measured by radioimmunoassay several times throughout the year and was compared to serum GH levels at each time. The amounts of irSRIF in extracts of the pituitary gland, hypothalamus, and telencephalon were found to be inversely related to seasonal changes in serum GH levels, such that irSRIF was highest in these regions when serum GH levels were lowest (November and February). Conversely, irSRIF in these regions was lower in May, June, and July when serum GH levels were highest. These results suggest that endogenous irSRIF in the pituitary and forebrain may participate in the regulation of seasonal changes in serum GH levels in the goldfish. In extracts from other brain regions (thalamus + midbrain and cerebellum + medulla), some changes in the amount of irSRIF were observed among the various sample times, but these variations were not related to changes in serum GH levels. In a second set of experiments, the origin of irSRIF fibers innervating the goldfish pituitary gland was examined by using brain lesioning techniques to destroy regions of the forebrain known to contain irSRIF perikarya and fibers, and subsequently measuring the amount of irSRIF in the pituitary gland. Lesions in the preoptic area of the forebrain resulted in increased serum GH levels concomitant with a decrease in pituitary irSRIF content. This provides direct evidence that the preoptic area is the origin of a somatostatinergic projection inhibiting GH secretion from the goldfish pituitary. Lesions centered in the nucleus lateral tuberis (NLT) pars anterioris did not influence serum GH levels or the pituitary content of irSRIF. In contrast, more posterior lesions centered in the NLT pars posterioris (NLTp) resulted in a dramatic reduction in the amount of irSRIF in the pituitary. This suggests that the majority of irSRIF projections to the goldfish pituitary pass through the area destroyed by the lesion centered in the NLTp; it is also possible that perikarya within this area may be the origin of at least some of the irSRIF-containing fibers in the goldfish pituitary. Together, results from the present study provide evidence of a functional relationship between circulating levels of GH and endogenous brain and pituitary irSRIF in the goldfish.

Inhibition by Prednisone of Growth Hormone (GH) Response to GH-Releasing Hormone in Normal Men

Glucocorticoids increase GHRH-stimulated GH secretion when added in vitro to cultured monkey, rat, and human pituitary cells and when injected in vivo into anesthetized rats. Yet, in man glucocorticoids inhibit linear growth and GH secretion. To clarify this apparent disparity and to determine if glucocorticoid stimulation can augment GH release in man after direct pituitary stimulation with GHRH, we administered 1 microgram/kg GHRH dosage to seven normal men before and after a 4-day course of prednisone (20 mg, orally, three times daily). The second GHRH test was done 12 h after the last dose of prednisone was given. Prednisone significantly inhibited the mean maximal increase in serum GH after GHRH treatment [20.7 +/- 4.5 (+/- SE) vs. 6.3 +/- 2.4 micrograms/L; P less than 0.01] as well as the GH value obtained by summing and averaging the individual means of the 15, 30, 45, 60, 75, and 90 min serum GH concentrations (11.1 +/- 1.2 vs. 4.3 +/- 0.9 micrograms/L; P less than 0.05). The mean serum insulin-like growth factor I and plasma glucose concentrations were not significantly altered by prednisone administration. These results together with previous in vitro findings imply that glucocorticoid-induced inhibition of GH secretion in man does not occur at the level of the pituitary gland, but, rather, at the hypothalamus or above.