Growth Hormone Response Curve Research Articles

Roasted Soybeans and an Estrogenic Growth Promoter Affect Growth Hormone Status and Performance of Beef Steers

This study investigated the effects of a roasted soybean (RSB)-supplemented diet and an estrogen implant (SYN; Synovex-S® ear implant, 20 mg estradiol benzoate plus 200 mg progesterone) in young crossbred beef steers on their performance and plasma growth hormone (GH) response to challenge injections of thyrotropin-releasing hormone (TRH) + GH-releasing hormone (GHRH). Twenty individually fed steers (body weight 255 ± 5 kg) were assigned to the following treatments: 1) no SYN and fed a soybean meal-supplemented diet, 2) no SYN and fed the RSB-supplemented diet, 3) plus SYN and soybean meal, and 4) plus SYN and RSB. Steers were fed 1.13 MJ metabolizable energy/kg metabolic body weight daily of an 18% protein diet. After a 5-wk growth period, all steers were challenged (intravenous injection) over a 3-wk period with three levels of a combination of TRH + GHRH (0.1 + 0.01, 1.0 + 0.1, 2.5 + 0.25 µg/kg body weight, respectively). After an additional 3 wk, steers were reimplanted and a second 5-wk growth period was followed by a single challenge of the 1.0 + 0.1 TRH + GHRH dose level. Plasma nonesterified fatty acid concentration was greater when steers were fed the RSB compared with soybean meal (265 vs. 205 µmol/L; P < 0.01; SEM = 9.5). Body weight gains for treatments 1, 2, 3 and 4 were 1.35, 1.21, 1.47 and 1.38 kg/d, respectively (RSB, P < 0.10; SYN, P < 0.07; SEM = 0.06). Gain/dry matter intake (g/kg) means were 184, 167, 197 and 184 (RSB, P < 0.04; SYN, P < 0.07; SEM = 7.5). Feeding roasted soybeans resulted in depressed area under the GH response curve [907, 555, 827 and 989 µg/(L*min) (SYN × RSB, P < 0.03; SEM = 117)] and depressed peak response (37.2, 26.6, 33.5 and 41.1 µg/L [SYN × RSB, P < 0.05; SEM = 4.5]), an effect alleviated by estrogen for young growing steers (Period 1) but not for heavier steers (Period 2).

Growth Hormone Response to Growth Hormone Releasing Hormone in Calves that Differ in Genetic Merit for Milk Yield

Holstein heifer, steer, and bull calves from control (CL) and select (SL) lines of cows that differed by more than 4000kg of milk during a 305-d lactation (SL>CL) were used to determine growth hormone (GH) response to 5 doses of GH releasing hormone (GHRH) and how this response was affected by gender, period (age), and genetic merit for milk yield. Doses (0, 2.5, 5, 10, and 20μg/100kg of BW) of a GHRH analog were assigned randomly to each heifer (4 CL, 4 SL), steer (4 CL, 4 SL), and bull (3 CL, 3 SL) calf and administered on consecutive days at approximately 3, 6, and 10 mo of age (periods; P1, P2, and P3). Jugular blood samples (n = 15) collected between −30 and 240min relative to GHRH administration were used to quantify area under the GH response curve (AUC) after subtracting mean prechallenge GH concentrations. Estimates of maximum response (Rmax) and sensitivity (ED50) to GHRH were obtained from the hyperbolic dose response curves (AUC vs. dose). Data were analyzed for effects of dose, line, period, gender, and their interactions with period as the repeated effect. Prechallenge GH concentrations were not affected by genetic line, gender, or period. The AUC was not affected by line, but decreased with period and increased with GHRH dose. The Rmax did not differ between lines or among genders, but decreased with period. The ED50 did not differ between lines or among periods, but heifers were more sensitive to GHRH than steers or bulls. Although GH response to GHRH has been identified as a potential indicator of genetic merit, it did not differ between these substantially different genetic lines.

Effects of dietary protein and growth hormone-releasing peptide (GHRP-2) on plasma IGF-1 and IGFBPs in Holstein steers

This study was conduct to determine the influence of dietary protein on the response of plasma insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding proteins (IGFBPs) to exogenous growth hormone releasing peptide-2 (GHRP-2 or KP 102) in Holstein steers. Eight 16-month-old Holstein steers were grouped by liveweight to two feeding treatments; high protein (HP; CP 1.38 kg/day and TDN 4.5 kg/day DM intake, n = 4) or low protein (LP; CP 0.66 kg/day and TDN 4.42 kg/day DM intake, n = 4). The experiment was a single reverse design whereby each group was injected twice daily with GHRP-2 (12.5 μg/kg body weight (BW)/day) or saline solution into the jugular vein for a 6-day period. Plasma IGF-1 in the HP group were higher than in the LP group ( P < 0.05), but plasma 34 kDa IGFBP-2 was lower in the HP than the LP group ( P < 0.05). The amplitude of the maximum growth hormone (GH) peaks responding to GHRP-2 injection were higher at day 1 than at day 6 of saline or GHRP-2 treatment in both LP and HP steers ( P < 0.05). The area under the GH response curve for 180 min after the GHRP-2 injection was not significantly different between the LP and the HP groups at days 1 and 6. A response in plasma IGF-1 concentration to GHRP-2 treatment in the HP group was observed at day 1 (198.9 ± 18.1 ng/ml), day 2 (195.2 ± 21.1 ng/ml) and day 6 (201.3 ± 14.8 ng/ml) ( P < 0.05). No increase in plasma IGF-1 was observed from GHRP-2 administration in the LP group. Although the response of plasma IGF-1 concentration to GHRP-2 administration was increased in the HP group ( P < 0.05), there was no apparent effect of GHRP-2 treatment on plasma 38–43 kDa IGFBP-3 and 34 kDa IGFBP-2 at days 2 and 6 of treatment. In conclusion, it is proposed that the 34 kDa IGFBP-2 is sensitive to dietary protein level and may play an important role in the regulation of circulating IGF-1 in ruminant. In addition, increased plasma IGF-1 concentration observed in the HP group in response to the GHRP-2 treatment did not appear to affect plasma IGFBPs.

Effects of Selection for Milk Yield on Growth Hormone Response to Growth Hormone Releasing Factor in Growing Holstein Calves

Bull and heifer calves (n=81) from genetic lines of Holstein cows that differed by more than 4000kg milk/305-d lactation were used to determine effects of selection for milk yield on growth hormone (GH) response to a GH releasing factor (GRF) analog. Calves received GRF (4μg/100kg BW) on 10, 56, 140, 196, 252, and 364±3 d of age. Jugular blood samples (n=15) were obtained from −30 to 120min relative to GRF administration. Area under the GH response curve (0 to 60min, AUC60) was quantified after subtracting mean prechallenge GH concentrations. Data were analyzed for effects of line, age, gender, and their interactions with PROC MIXED of SAS for repeated measures and incorporated the spatial power law for unequally spaced data with age as the repeated effect. Means were considered different when P<0.05. Prechallenge GH concentrations did not differ between lines, were greater in bulls than heifers (4.6 vs. 3.7ng/ml), and decreased with age. The AUC60 decreased with age but did not differ between lines. Heifers responded more to GRF than bulls (1550 vs. 1336ng×min/ml). Peak GH concentration decreased with age and was less in bulls than heifers (54.7 vs. 62.1ng/ml) but did not differ between lines. Although plasma GH has been identified as an inheritable trait, we conclude the GH variables measured in this study were not useful in predicting genetic merit of calves from these substantially different lines of cows.

Plasma growth hormone (GH) responses after administration of the peptidergic GH secretagogue KP102 into the oral cavity, rumen, abomasum and duodenum in adult goats

The study was performed to determine whether orally administered KP102 (also known as GHRP-2) stimulates GH release in adult goats, and how the orally administered KP102 passes through the digestive tract and stimulates GH release in ruminant animals. Five mg/kg body weight (BW) of KP102 dissolved in 9 ml of saline were administered into the oral cavity, rumen, omasum and duodenum of adult goats, and GH release after administration of KP102 was examined. The GH levels were significantly elevated at 20 min after administration of KP102 into the oral cavity, and plasma concentrations of GH remained significantly elevated until 60 min (P < 0.05). The GH levels after administration of KP102 into the abomasum were variable. However, the GH level tended to increase within 30 min after administration, and were significantly higher than those of controls after 120 to 150 min (P < 0.05). The GH levels after administration of KP102 into the duodenum were significantly elevated at 40 min after administration, and plasma concentrations of GH remained significantly elevated until 140 min (P < 0.05). The administration of KP102 into the rumen failed to stimulate GH release. The GH response curves (AUC) produced after administration of KP102 into the abomasum or duodenum were 2.2-fold greater than those for after administration into the oral cavity (P < 0.05). The oral administration of 5 mg/kg BW of KP102 in the powder state, not dissolved in 9 ml of saline, failed to stimulate GH release. These results suggested that orally administered KP102 dissolved in saline transiently stimulates GH release in adult goats, and this phenomenon might be due to small amounts of the peptides entering directly into the abomasum with liquid bypassing the rumen.

Growth Hormone-Releasing Peptide-2 (GHRP-2) Acts Synergistically with Growth Hormone-Releasing Hormone (GHRH) to Release Growth Hormone (GH) in Swine

The aim of the present study was to examine the growth hormone (GH) response to the combined and repeated administrations of growth hormone-releasing peptide-2 (GHRP-2) plus growth hormone releasing hormone (GHRH) in swine. Six cross-bred castrated male swine, 130-135 days of age were used in this study. Animals were given a single intravenous (i.v.) injection of either GHRP-2 (30μg/kg BW), GHRH (1μg/kg BW) and GHRP-2 (30μg/kg BW) plus GHRH (1μg/kg BW) or 5ml saline (served as control) in random order with two days apart. GHRP-2 or GHRH alone and in combination with together stimulated the release of GH in swine. The peak concentrations of GH and areas under the GH response curve (GH AUC) for 120min after these treatments were significantly higher (P<0.01) than those in controls. The combined administration of these two peptides [GHRP-2 (30μg/kg BW) and GHRH (1μg/kg BW)] resulted in a GH AUC significantly greater than the arithmetic sum of those following their separate administrations (P<0.05), demonstrating the synergistic effect for GH release. GH responses to two successive i.v. injections of GHRP-2 (30μg/kg BW) plus GHRH (1μg/kg BW) at 2h interval in swine were increased after each injection; however, peak concentration of GH and GH AUC for 120min after the second injection were significantly lower (P<0.01) than those after the first injection. These results of the present study indicated that the combined administration of GHRP-2 and GHRH synergistically stimulates the release of GH in swine, and the GH responses to the co-administration of these two peptides decrease after the repeated injection. These findings suggest that GHRP-2 and GHRH act through different receptors and intracellular signal transduction and can be used together for stimulating further release of GH in swine.

Effects of the administration of growth hormone-releasing peptide-2 (GHRP-2) orally by gavage and in feed on growth hormone release in swine

The experiments were conducted to determine the effects of the administration of growth hormone-releasing peptide-2 (GHRP-2, also named KP102), both orally by gavage and in feed, on the release of growth hormone (GH) in swine and to investigate whether attenuation of the GH response occurs after short-term treatment with the peptide in feed. In the first experiment, saline or GHRP-2 at doses of 1, 4.5 and 9 mg/kg body weight (BW) was dissolved in 15 ml saline and administered orally as a bolus by gavage to cross-bred castrated male swine ( n = 6). Orally administered GHRP-2 stimulated dose-related increases in peak concentrations of GH, with a return to basal by 120 min. After administering GHRP-2 orally, peak concentrations of GH and areas under the GH response curves (GH AUCs) for 180 min were higher (P < 0.05) than those in saline controls. In Experiment 2, GHRP-2 at doses of 0 (served as control), 1, 4.5 and 9 mg/kg BW was mixed in 150 g of feed and offered to cross-bred castrated male swine ( n = 6) at 0900 hr and 1700 hr daily for a 3-d period. Administration of 1 mg/kg BW GHRP-2 to swine in feed failed to stimulate the release of GH, but GHRP-2 at doses of 4.5 and 9 mg/kg BW significantly (P < 0.05) increased plasma concentrations of GH after initial and final treatments at 0900 hr on Days 1 and 3 of treatment, respectively. Peak concentrations of GH and GH AUCs for 180 min after the initial and final treatments in the 4.5 and 9 mg/kg BW GHRP-2-treated swine were higher (P < 0.05) than those in controls. After 3 d of treatment with GHRP-2 in feed at doses of 4.5 and 9 mg/kg BW, GH responses to the peptide were maintained. The results of the present study indicate that the administration of GHRP-2 orally by gavage and in feed stimulates the release of GH in swine, and that the GH-releasing effect of the peptide does not become desensitized after short-term administration in feed.

Growth hormone responses during strenuous exercise: the role of GH-releasing hormone and GH-releasing peptide-2.

This study was designed to investigate the role of two effective releasers of growth hormone (GH): GHRH and GHRP-2 during exercise (EX). Eight healthy male subjects (ages: 22 +/- 1.2 (mean +/- SD) yr, BMI: 22.5 +/- 2.2 kg x m(-2)) were exposed to maximally stimulating dose of 100 microg GHRH iv, and 200 microg GHRP-2 iv, during incremental EX on a cycle ergometer to exhaustion. GH responses after EX alone were compared with the responses after the combined administration of the same EX plus GHRH, EX plus GHRP-2, and EX plus GHRH plus GHRP-2. Blood samples were obtained in the fasted state at intervals for 2 h postexercise and the area under the GH response curve (AUC) was calculated by trapezoidal integration. Significant differences (P < 0.003) were observed between the AUCs after administration of EX alone (mean +/- SEM): 2,324 +/- 312 microg x L(-1) 120 min, after EX plus GHRH: 6,952 +/- 1,083, after EX plus GHRP-2: 14,674 +/- 2,210, and after the combination EX plus GHRH plus GHRP-2: 17,673 +/- 1,670. However, AUCs after each combination did not differ significantly from those after arithmetical addition of each separate stimulus, indicating that the mechanisms of the respective stimuli do not interact. Linear regression analysis on mean GH responses between 20 and 30 min after the start of EX showed that EX alone and GHRH alone explain about 59% (adj. R2) of the GH response to the combination EX plus GHRH. The ratio of the respective regression coefficients (GHRH vs EX) was about 2:1 (instead of 1:1), indicating that EX seems to potentiate the activity of GHRH. GHRH alone and EX alone also explained about 74% of the response to the combination EX plus GHRP-2. In the latter response, a synergistic action of GHRP-2 on GHRH could be observed. The data indicate that under strenuous EX conditions, endogenous GHRH activity causes a further increase of GH release. A GHRP-2 mediated mechanism in the central neuroendocrine regulation acts as a "booster," possibly by stimulating the effects of GHRH and/or an unknown hypothalamic factor, as well as by stimulating the pituitary GH release directly.

Serum somatotropin concentrations in Holstein heifers administered growth hormone-releasing factor and somatostatin

AbstractDose-response experiments were designed to determine the dosage of somatostatin (SRIF) necessary to alter serum growth hormone (GH) response to administration of GH-releasing factor (1·44; GRF) in cattle. The objective of this experimentation was to develop a GRF/SRIF challenge model that might be useful in early identification of animals which are genetically superior for milk production traits. In experiment 1, calves received either 0, 5 or 10 /JLg GRF per 100 kg body weight (BW) or GRF 1·29 at 1 ug per 100 kg BW. Both the 5 and 10 ug GRF per 100 kg BW dosages increased GH concentrations (P &lt; 0·05). In experiment 2, animals received 3 ug GRF per 100 kg BW concurrent with administration of 0, 0·5, 1 or 2 ug SRIF per 100 kg BW at 0 min, with second dosage of GRF at +120 min. Administration of SRIF in those dosages did not alter GH response to GRF. In experiment 3, animals received 5 ug SRIF per 100 kg BW at -2, -1, 0 or +1 min relative to 3 ug GRF per 100 kg BW, with a second GRF injection at +120 min. No differences (P &lt; 0·05) were found in response due to timing of SRIF administration. In experiment 4, animals were administered 0, 5, 10 or 20 Xg SRIF per 100 kg BW concurrent with 3 ug GRF per 100 kg BW. SRIF delayed (P &lt; 0·05) the occurrence of maximum GH concentrations but did not affect the maximum concentration nor the area under the GH response curve (AUC) following either the first or second GRF injection. Utilizing data from experiment 4, individual animal response to GRF was reasonably consistent, as repeatabilities of AUCs for 1 h following first and second GRF injections were 0·80 and 0·65, respectively. Furthermore, sufficient among-animal variation existed so that animals could be distinguished from each other. Thus we conclude the method described herein might be useful in identifying superior dairy calves but accuracy would potentially be enhanced by collecting blood samples more frequently during the 20 min immediately after GRF injection.

Acipimox potentiates growth hormone response to growth hormone-releasing hormone by decreasing serum free fatty acid levels in hyperthyroidism

Hyperthyroidism is associated with an impairment of growth hormone (GH) responses to secretagogues. The aim of this study was to evaluate the effect of acipimox, an antilipolytic agent able to decrease free fatty acids (FFA), on GH response to GH-releasing hormone (GHRH) in hyperthyroid and normal control subjects. We studied six men with hyperthyroidism; seven normal men served as control subjects. Each subject underwent treatment with (1) 2 tablets of placebo orally or (2) 500 mg acipimox orally, 120 minutes before intravenous (IV) injection of 1 μg/kg GHRH-(1–29)NH 2. GH response to GHRH in hyperthyroid patients was markedly reduced; the mean peak GH response (9.6 ± 1.0 μg/L) and the area under the GH response curve (12.9 ± 1.3 μg/L × 2 h) were lower than those of control subjects (25.7 ± 1.8 μg/L, P < .05; 28.7 ± 2.1 μg/L × 2 h, P < .05). Hyperthyroid patients had higher baseline levels of plasma FFA than control subjects (998.0 ± 38.9 v 498.0 ± 36.0 μEq/L, P < .01). Acipimox decreased FFA levels in both hyperthyroid and control subjects; the lowest FFA levels of hyperthyroid subjects induced by acipimox were similar to those of control subjects. After acipimox pretreatment, GH responses to GHRH increased significantly ( P < .05); the mean peak plasma GH level (25.9 ± 4.6 μg/L) was similar to the peak GH levels of control subjects during the GHRH test, and the area under the GH response curve (41.1 ± 6.7 μg/L × 2 h) was even higher than that of control subjects with the GHRH test. However, the enhanced GH responses of hyperthyroid patients were still lower that those of control subjects during the acipimox plus GHRH test. We demonstrated that the decreased FFA levels induced by acipimox potentiate somatotrope responsiveness, likely acting at the pituitary level. Our results indicate that high FFA levels are responsible for impaired GH responses to GHRH in hyperthyroidism.

Effects of acute administration of growth hormone-releasing hormone (GHRH) and oxytocin on somatotroph cells in sheep: Morphometric study and growth hormone (GH) secretion

In this work, the combined use of the morphometric study of somatotroph cells and plasma GH levels provided new data for the interpretation of the role played by OT and GHRH on GH cells. GHRH 1-29 (15 micrograms/kg), oxytocin (2.5 IU animal) or 1 ml saline solution were administered to male lambs. The GH plasma concentration was measured by RIA and for the morphometric study the cellular area, nuclear area and volume density of the somatotroph cells were measured in 1 micron semi-thin sections immunolabeled with avidin-biotin technique (ABC). The area under the GH response curve for 3 hours after injection was similar in both saline and OT-treated animals (24.8 +/- 9.1 and 31.4 +/- 14.7 micrograms/ml, respectively) and much lower than that observed in GHRH-treated animals (445.5 +/- 126.7 micrograms/ml). The cell area of somatotrophs was smaller in the GHRH-treated lambs and larger in the OT-treated lambs than in the control lambs (71.47 +/- 1.56, 91.42 +/- 1.72 and 83.1 +/- 1.74 microns 2, respectively). A similar change was observed in the nuclear area; it decreased in the GHRH-treated lambs (21.61 +/- 0.52 microns 2) and increased in the OT-treated lambs (25.45 +/- 0.68 microns 2) with respect to the control group (23.75 +/- 0.44 microns 2). No significant differences were found in volume density.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone response after administration of growth hormone-releasing factor to proven dairy sires

To estimate the potential of GH response to administration of growth hormone (GH)-releasing factor (GRF) as a predictor of genetic merit, two experiments, utilizing proven AI dairy sires of differing genetic merit for milk production, were conducted. In a first experiment, bulls of superior genetic merit [S; n=4; genetic merit for economic value of product (MFP$)=$227] or inferior genetic merit (I; n=4; MFPS=$94) were administered, three dosages of GRF (0, 5.5 and 11 μg GRF · 100 kg BW −1). Each bull received one dosage of Ro23-7863, an hGRF (1–29) analog, on each of three consecutive days. Area under the GH response curve (AUC) from S bulls following 5.5 or 11 μg GRF were greater (P<0.01) than AUC from I bulls. In a second experiment, a single dosage of GRF (4 μg GRF · 100 kg BW −1) was administered to sires of superior (S; n=8; MFPS=$204), average (A; n=8; MFP$=$149) or inferior (I; n=8; MFPS=$74) genetic merit. There was no effect (P>0.05) of genetic group on preinjection AUC, however, AUCs following GRF were greater (P < 0.01) from S and A sires compared with I sires (1925 and 1676 vs. 549 ng min ml −1, respectively). Therefore, GH response to exogenous GRF administration may be a useful tool in identifying dairy bulls with superior transmitting ability for milk production traits.

Effect of age and intake on growth hormone kinetics in dairy heifers

The effects of aging and intake on growth hormone (GH) kinetics and GH-releasing factor (GRF)-induced GH concentrations were studied in two groups of 12 Holstein heifers each (80 d, 85 kg: young; and 273 d of age, 246 kg: old). Each group was then equally subdivided into full-fed (FF) and restricted-fed (RF) subgroups. After 11 d of intake treatment, animals were infused for 3 hr with GH (1.5 mg/hr) in order to calculate GH metabolic clearance rate (MCR), secretion rate (SR) and half-life ( t 1 2 ). Two d later, total plasma volume was determined and the following day, all heifers received a GRF challenge (5 μg/kg i.v.). The following values are LSM ± SE for young-FF, young-RF, old-FF and old-RF. Rate of secretion was not affected by any treatment, averaging 1.51, 1.25, 1.34, and 1.40 ± .23 μg/min. Aging increased (P<.01) MCR (186, 159, 382, and 300 ± 21 ml/min) and increased plasma volume (P<.01), which resulted in lower basal GH concentrations. Aging also decreased (P<.01) the area under the GH response curve following GRF injection (AUC: 12442, 21114, 5155, and 6308 ± 1776 ng · min/ml) but did not affect average GH quantity in the plasma after the GRF challenge. Feed restriction decreased (P<.05) MCR, but not enough to affect basal GH concentrations. However, feed restriction increased GRF-induced GH concentrations in young heifers only; since all GH kinetic variables were similarly affected by intake in old and young heifers, this effect of feed restriction in the young heifers probably resulted from a higher pituitary secretion of GH when challenged with GRF. Concentrations of insulin, glucagon, glucose, insulin-like growth factor-I (IGF-I) and free fatty acids (FFA) were determined. There was a correlation (P<.001) between IGF-I and GH MCR (r 2=.65) and AUC (r 2=−.66), and a correlation between FFA and GH secretion rate (r 2=−.41, P<.05). The AUC was related to the MCR (r 2=−.67, P<.001). These data therefore indicate that post-secretory metabolism of GH plays an important role in determining GH concentrations in peripheral circulation. The effect of aging (from 3 to 9 mo) on GH concentrations is mostly due to increased MCR and plasma volume, while feed restriction affects the kinetics of GH and the GRF-induced secretion.

Evaluation of the biological potency of new agmatine analogs of growth hormone-releasing hormone in the bovine.

Four new growth hormone-releasing hormone (GHRH) analogs with C-terminal agmatine were compared with the parent human GHRH(1-29)NH2 fragment to assess their abilities to increase serum concentrations of growth hormone (GH) in the bovine. The four analogs were: [D-Ala2, Nle27] GHRH(1-28)Agm (JG-73); [desNH2-Tyr1, Ala15, Nle27] GHRH(1-28)Agm (MZ-2-51); [desNH2-Tyr1, Ala15, D-Lys21, Nle27] GHRH(1-28)Agm (MZ-2-75); and [desNH2-Tyr1, D-Lys12,21, Ala15, Nle27] GHRH(1-28)Agm (MZ-2-87). The special characteristic of all four GHRH analogs is that arginine was replaced by agmatine (Agm) in Position 29. Five pregnant Holstein cows received these peptides subcutaneously at the following doses: 0.0156, 0.0625, 0.25, 1, and 4 micrograms/kg body wt. Each cow received each analog-dose combination according to a 5 x 5 Greco-Latin square design repeated for the 5-week treatment. Each cow also received saline vehicle only at the end of the 5-week treatment. Blood samples were collected from 30 min before until 360 min after treatment injection. Total area under the GH response curves for the 6-hr sampling period for each dose of each GHRH analog was compared. There was a linear dose-dependent GH release in response to hGHRH(1-29)NH2 and its four GHRH(1-28)Agm analogs. At the dose of 0.25 micrograms/kg, two GHRH analogs, JG-73 and MZ-2-75, stimulated greater GH release than hGHRH(1-29)NH2 (P less than 0.05). No differences were seen at the two lowest doses, 0.0625 and 0.156 micrograms/kg. When both total area under the GH response curves and GH peak amplitudes for each treatment were averaged for all doses, JG-73 and MZ-2-75 stimulated greater GH release than hGHRH(1-29)NH2 (P less than 0.05). In summary, three GHRH(1-28)Agm analogs, JG-73, MZ-2-75, and MZ-2-51, were found to be 11.8, 11.3, and 6.5 times more potent, respectively, on a weight basis, than hGHRH(1-29)NH2 in stimulating the release of GH in cows.

Effect of triglycerides on growth hormone (GH)-releasing factor-mediated GH secretion in newborn calves

The effect of triglycerides (Tg) on GRF-mediated GH secretion was examined in 2 groups of twelve ten-day old male calves. Twelve calves were intravenously infused with a lipid-heparin solution (5 mg Tg and 0.3 IU heparin/kg body wt/min for 90 min). The twelve control calves received in the same way, the same volume of saline. Thirty minutes after the start of infusion, GRF 1–29 (human amide, 0.16 μg/kg body wt) was intravenously injected in six animals of each group. Mean plasma GH levels reached peak concentrations in the 2 groups 5 min after GRF injection. However the area under the GH response curve, when lipid-heparin was given, was significantly diminished compared to the response when saline was given. In the same time, lipid-heparin treatment increased plasma SRIF concentration. These data suggest that an increase in plasma Tg concentration, induced by lipid-heparin infusion, inhibits GRF-mediated GH secretion, possibly through stimulation of SRIF secretion.

Synergism and diurnal variations of human growth hormone-releasing factor (1–29)NH 2 and thyrotropin-releasing factor on growth hormone release in dairy calves

Sixteen male Holstein calves averaging 168 kg body weight (BW) were used to determine the effects of human growth hormone-releasing factor (1–29)NH 2 (hGRF (1–29)NH 2; .22 μg/kg BW), thyrotropin-releasing factor (TRF; .165 μg/kg BW) or hGRF (1–29)NH 2 plus TRF (.22 and .165 μg/kg BW, respectively) on growth hormone (GH) release in animals exposed to 16 hr of light (L): 8 hr of dark (D) (lights on at 0100 hr) and hGRF plus TRF (.22 and .165 μg/kg BW, respectively) in animals exposed to 8L:16D (lights on at 0900 hr). For each treatment, times of iv injection were 0400, 1000, 1600 and 2200 hr. In animals exposed to 16L:8D, average GH peaks reached after hGRF (1–29)NH 2 or TRF injections were 49.7 and 32.0 ng/ml while the area under the GH response curve (AUC) were 1247 and 1019 ng/ml ∗min, respectively. There was no significant effect of times of injection on GH release following the separate injection of hGRF (1–29)NH 2 or TRF. In animals exposed to 16L:8D, GH peaks and AUC after hGRF plus TRF injections were 226.4, 189.2 and 116.8 ng/ml, and 4340, 3660 and 2415 ng/ml ∗min at 0400, 1000 and 1600 hr (lights on), respectively but only 42.3 ng/ml and 1692 ng/ml ∗min at 2200 hr (lights off). In animals exposed to 8L:16D, GH levels and AUC after hGRF plus TRF injections reached 177.5 and 180.5 ng/ml, and 2759 and 3704 ng/ml ∗min at 1000 and 1600 hr (lights on) but only 84.0 and 72.7 ng/ml, and 1544 and 1501 ng/ml ∗min at 0400 and 2200 hr (lights off), respectively. These results demonstrated that hGRF (1–29)NH 2 and TRF can act in synergy to potentiate GH release in dairy calves. This synergistic action occurred only when both peptides were injected during the lighted phase of short and long day photoperiods.

Growth hormone (GH) response to a single intravenous injection of synthetic GH-releasing hormone in prepubertal children with growth failure.

In this collaborative study involving 27 European medical centers, the plasma GH response to a single iv bolus dose of 2 micrograms/kg BW synthetic GHRH-(1-44)NH2 was determined in 574 children with growth failure of various etiologies. Analysis of the plasma GH response to GHRH was performed in 394 validated prepubertal children; these children were subdivided into 3 groups according to the degree of GH deficiency assessed within 6 months by conventional provocative tests (insulin, arginine, etc.): normal GH status (n = 210), partial GH deficiency (n = 73), or severe GH deficiency (n = 111). The mean peak GH values (+/- 2 SEM) after GHRH treatment in the three groups were 45.8 +/- 4.8, 29.2 +/- 6.3, and 16.8 +/- 3.1 microU/mL, respectively, and were greater than those after the conventional tests. The GH responses were consistent with the degree of GH deficiency based on the responses to the conventional tests. In addition, the areas under the GH response curves in the three groups were significantly different (P less than 0.0001). Among children with severe idiopathic GH deficiency 77% had a peak plasma GH level after GHRH above 10.0 microU/mL and 39% had a peak GH above 20.0 microU/mL. In these children, a single GHRH injection provides information on both their GH secretory capacity and the putative supresellar etiology of their GH deficiency, and may be of potential therapeutic value.

Serum growth hormone and nitrogen metabolism responses in young bull calves infused with growth hormone-releasing factor for 20 days

Intravenous infusion of growth hormone (GH)-releasing factor (GRF) sustains elevated serum GH for at least 5 days in young Holstein steers, but the effects of extended infusion of GRF on serum GH and nitrogen (N) metabolism have not been determined. Thirteen Dutch-Friesian bull calves (148 ± 1.5 kg) were assigned randomly to receive daily either 0 or 3.6 mg GRF (hGRF 1–44NH 2; U-68420) in saline as a continuous infusion for 20 days. Calves were fed milk replacer twice daily while housed indoors in wooden-slatted floor box crates (metabolism cages). Nitrogen determinations were made on daily feed, feces, and urine samples which were pooled for days 9 to 14 of treatment. Concentrations of GH were quantified in blood samples collected at 20 min intervals for 8 hr on day 1, 10 and 20. The infusion of GRF increased baseline GH (P<.07), the number of GH pulses (P<.0001), the amplitude of the GH pulses (P<.001), and area under the GH response curve (P<.0002). Within GRF-infused calves baseline GH (P<.0001) and area under the GH response curve (P<.006) were greater on day 20 than on day 1 or 10 (day × treatment interaction, P<.04). Area under the GH response curve was similar on each sampling day in saline-infused calves, but baseline GH was higher (P<.03) on day 20 than either day 1 or 10. Infusion of GRF increased episodic GH secretion in spite of limited pulsatile activity in saline-infused calves. On days 9–14, infusion of GRF decreased the excretion of urinary N (P<.02) and improved N balance (P<.04) without affecting N intake, fecal N, or the coefficient of N digestibility compared to saline-infused calves. In the present study, GRF administered as a continuous iv infusion for 20 days maintained elevated serum GH concentrations, conserved the episodic GH pattern, and improved N balance in young bull calves. The findings that (1) the pituitary does not become refractory to continued exposure to GRF and (2) a positive effect on N metabolism clearly make GRF or an analog an attractive alternative to exogenous GH as a means to improve animal production.

Response of growth hormone release to human growth hormone-releasing factor and its analogs in the bovine.

Responses of growth hormone (GH) release to synthetic human growth hormone-releasing factor (hGRF)-44-NH2 analogs were determined, and the GH-releasing potency based on dose per kg of body weight (bw) was compared with that of hGRF-44-NH2 in female dairy calves. Four- and 12-month-old calves were injected intravenously with 0.25 microgram of hGRF-44-NH2 or its analogs per kg of bw. Blood samples were collected before, and during 180 min after each injection, and plasma GH concentrations were measured by radioimmunoassay. Areas under the GH response curves for 180 min after injection of hGRF-44-NH2 and its analogs were used as an index of the GH-releasing potency of each peptide. The GH-releasing potency of hGRF(1-26)-NH2 was significantly lower than that of hGRF-44-NH2 (P less than 0.05). On the other hand, hGRF(1-29)-NH2 possessed similar potency to hGRF-44-NH2. [D-Tyr1]-hGRF-44-NH2 showed prolonged GH-releasing activity, though its potency was similar to that of hGRF-44-NH2. Also, [D-Ala2]-hGRF(1-29)-NH2 exhibited prolonged GH-releasing activity, and its potency was 2.5 (P less than 0.05) and twice (P less than 0.05) as great as that of hGRF-44-NH2 and hGRF(1-29)-NH2, respectively. These results demonstrate that the N-terminal 29 amino acid residues of hGRF possess the activity site required for full GH release in vivo, and [D-Ala2]-hGRF(1-29)-NH2 has longer and greater activity, on a dose basis, than hGRF-44-NH2 in the calves.

Deranged alpha-adrenergic regulation of growth hormone secretion in poorly controlled diabetes: reversal of the exaggerated response to clonidine after continuous subcutaneous insulin infusion.

Elevated plasma growth hormone (GH) and peripheral catecholamine levels are frequently observed in poorly controlled, insulin-dependent diabetes. Since the alpha adrenergic system plays an important role in hypothalamic regulation of GH secretion, we tested the hypothesis that altered central adrenergic activity contributes to the increased GH concentrations in diabetes. Clonidine, an alpha-adrenergic agonist, was administered to nine poorly controlled, young diabetic patients (age 12-19 yr) before and after 1 wk of continuous subcutaneous insulin infusion pump therapy. As expected, continuous subcutaneous insulin infusion lowered mean 24-h plasma glucose (from 203 +/- 21 to 112 +/- 7 mg/dl, p less than 0.01) and GH (from 17.7 +/- 2.1 to 9.2 +/- 1.2 ng/ml, p less than 0.01) to values observed in normal controls. In the diabetic patients during conventional treatment, both the peak plasma GH level postclonidine (48.3 +/- 8.7 ng/ml) and the incremental area under the GH response curve (3.23 +/- 0.58 mg X min/ml) were significantly increased above normal control values (25.2 +/- 2.1 ng/ml, p less than 0.05 and 1.63 +/- 0.11 mg X min/ml, p less than 0.0025, respectively). In contrast, the GH response to clonidine was indistinguishable from normal after only 1 wk of intensified insulin treatment. Our findings support the contention that metabolic control of diabetes influences hypothalamic regulation of GH secretion and suggests that such alterations are related, at least in part, to changes in central alpha-adrenergic activity.