GHRH Analog Research Articles

Predicting bull growth performance and carcass composition from growth hormone response to growth hormone-releasing hormone.

Development of practical, physiologically based methods that provide an early, yet accurate, evaluation of a bull's genetic merit could benefit the beef industry. The use of GH response to a single, acute dose of GHRH was evaluated as a predictor of future growth performance and carcass characteristics of weanling bulls. Fifty-six Angus bulls averaging 229 d (SD = 27) of age were administered three doses i.v. (0, 1.5, and 4.5 microg/100 kg BW) of human GHRH (1-29) analog in a Latin square design balanced for residual effects. Blood samples were collected via jugular catheter at -60, -45, -30, -15, 0, 5, 10, 15, 30, 45, 60, 90 and 120 min relative to GHRH injection. Serum concentrations of GH were plotted over time. Response to GHRH was calculated as the area under the GH response curve (AUC-GH) using the trapezoidal approximation. Relationships between AUC-GH, weaning weight adjusted to 205 d of age (205-d WW), and direct weaning weight EPD (WWEPD) versus age-adjusted BW (BWadj), ADG, and carcass measurements from a 140-d growth performance test were evaluated using simple linear regression. A positive correlation between AUC-GH and ADG and an inverse relationship between AUC-GH and carcass fat were observed. The present study provides evidence that AUC-GH is a better predictor of future growth performance in beef bulls than 205-d WW or WWEPD values. Thus, GH response to GHRH is associated with subsequent growth and may be a useful tool for sire selection in beef production.

Incorporation of D-Ala2 in growth hormone-releasing hormone-(1-29)-NH2 increases the half-life and decreases metabolic clearance in normal men.

D-Ala2-GHRH-(1-29) has increased binding affinity and exhibits enhanced biological activity in man. It is not known whether changes in the metabolic clearance of this and other GHRH analogs contribute to their increased biological activity. GHRH-(1-29)-NH2 and D-Ala2-GHRH-(1-29)-NH2 were administered by constant iv infusion at a rate of 25 ng/kg.min to 10 normal men. Blood was sampled during the 90-min infusion and for 20 min afterward and assayed for the infused analog. The MCR of the D-Ala2 analog (mean +/- SE) was significantly less (21 +/- 1.2 mL/kg.min) than that of GHRH-(1-29)-NH2 (39.7 +/- 3.9 mL/kg.min; P < 0.001). The disappearance half-time of the D-Ala2 analog was 6.7 +/- 0.5, whereas that of GHRH-(1-29)-NH2 was 4.3 +/- 1.4 min (P < 0.05). These findings demonstrate that the D-Ala2 substitution contributes to the enhancement of biological activity by reducing metabolic clearance.

Effects of continuous and repetitive administration of a potent analog of GH-RH(1-30)NH2 on the GH release in rats.

We examined the desensitization and/or sensitization phenomenon in the pituitary GH responsiveness induced by continuous infusion and multiple pulses at different frequencies of a potent GH-RH analog [D-Ala2, Leu15, Nle27, GABA30-GH-RH(1-30)amide]. Further, we investigated the correlation between doses and GH responses, as well as between pulse frequency and GH responses in male rats in vivo and in vitro. Long-term, continuous administration was attained by osmotic minipumps releasing low and high doses of the analog for 14 days. The effects of repetitive administration of the GH-RH analog on the pituitary GH release was investigated by injecting 4-6 pulses of the analog at different doses and pulse frequencies. The in vitro experiments were performed in the superfused rat anterior pituitary cell system. Pituitary cells were challenged with continuous, repetitive and simultaneous continuous and repetitive perfusion of the analog. Continuous infusion with low doses of the GH-RH analog in vivo induced sensitization of the pituitary GH-secretory responsiveness and resulted in moderately increased GH releases (129% of the control) to additional bolus injections of the same analog, whereas continuous stimulation of the pituitary with high doses of the GH-RH analog evoked desensitization and resulted in blunted GH responses (29% of the control). Despite the desensitization of the pituitary GH-secretory responsiveness, high doses of the analog elevated the serum GH concentration to 310% and induced acceleration of body weight gain (160% of the control). Repetitive pulsatile administration of the GH-RH analog evoked both sensitization and desensitization of the pituitary GH-secretory responsiveness, depending on the dose and pulse frequency administered.(ABSTRACT TRUNCATED AT 250 WORDS)

A new target for growth hormone releasing-hormone action in rat: the Sertoli cell.

A GHRH-like mRNA and peptide (t-GHRH) have been detected in rat and human testis. In rat, t-GHRH mRNA is localized to developing spermatogenic cells. We predicted that the most likely target cell of t-GHRH action would be the Sertoli cell. To test this prediction, we evaluated GHRH action on Sertoli cell function. Rat GHRH at a concentration of 10 nM or 100 nM stimulated cAMP production 2-fold over control levels after a 30 min incubation. This stimulation was obliterated by preincubation with a 10-fold excess of the GHRH antagonist (N-Ac-Tyr1, D-Arg2)-GRF(1-29)-NH2. The effect of treatment with [His1,Nle27]GHRH(1-32)-NH2, a GHRH analog, on Sertoli cell mRNAs was also assessed. Treatment with the analog significantly increased levels of c-fos and steel factor (the product of the Steel gene, also termed SCF) mRNAs above controls, but had no effect on sulfated glycoprotein-2 mRNA. We conclude that GHRH acts via adenylate cyclase to modulate specific Sertoli cell products, possibly as part of a network of local interacting factors controlling Sertoli and germ cell function.

A new target for growth hormone releasing-hormone action in rat: the Sertoli cell

A GHRH-like mRNA and peptide (t-GHRH) have been detected in rat and human testis. In rat, t-GHRH mRNA is localized to developing spermatogenic cells. We predicted that the most likely target cell of t-GHRH action would be the Sertoli cell. To test this prediction, we evaluated GHRH action on Sertoli cell function. Rat GHRH at a concentration of 10 nM or 100 nM stimulated cAMP production 2-fold over control levels after a 30 min incubation. This stimulation was obliterated by preincubation with a 10-fold excess of the GHRH antagonist (N-Ac-Tyr1, D-Arg2)-GRF(1-29)-NH2. The effect of treatment with [His1,Nle27]GHRH(1-32)-NH2, a GHRH analog, on Sertoli cell mRNAs was also assessed. Treatment with the analog significantly increased levels of c-fos and steel factor (the product of the Steel gene, also termed SCF) mRNAs above controls, but had no effect on sulfated glycoprotein-2 mRNA. We conclude that GHRH acts via adenylate cyclase to modulate specific Sertoli cell products, possibly as part of a network of local interacting factors controlling Sertoli and germ cell function.

Response to a growth hormone-releasing hormone analog in heifers treated with recombinant growth hormone

Sixteen pregnant Holstein heifers (430kg) were used to determine the effect of long-term administration of a bovine growth hormone (bGH) made by recombinant DNA technology on the ability of a bolus injection of a growth hormone-releasing hormone analog (Ac-His-1, D-Ala-2, Nle-27, GHRH(1–29 NH 2) to increase serum GH. Eight heifers received a daily intramuscular injection of bGH (50 mg/day) for 5 months while the other half received a daily injection of physiological saline (control) over the same period. On the last day of bGH treatment and 1, 5, 10 and 25 days after the cessation of bGH treatment, five heifers from each group were challenged with GHRH analog and the response to this releasing hormone analog was measured. Basal GH concentrations were elevated on the last day of treatment in bGH-treated heifers and declined to concentrations similar to control heifers by 1 day after cessation of treatment. Response to GHRH analog was impaired by bGH during the last day of treatment and one day later. Responsiveness returned to a level similar to controls by 5 days after the end of bGH treatment. Response to GHRH analog was lessened during the period of bGH treatment but there were no long term effects on the animals' ability to respond to the releasing hormone.

Growth hormone responses to growth hormone-releasing hormine (1–29)-NH 2 and a D-Ala 2 analog in normal men

Synthetic analogs of growth hormone-releasing hormone, GHRH(1–29)-NH 2 and D-Ala 2 GHRH(1–29)-NH 2 were administered as a bolus intravenous injection to five normal men in a dose range of 0.015 to 0.5 μg/kg body weight. Vehicle only was administered in a control study. Peak responses to GHRH analogs occurred at 15 or 30 min. An increase in the integrated plasma growth hormone (GH) response was observed at each dose. The dose-response curve of GHRH(1–29)-NH 2 indicated that it has a similar molar potency to GHRH(1–40) and GHRH(1–44). The potency of D-Ala 2 GHRH(1–29)-NH 2 was approximately twice that of GHRH(1–29)-NH 2. Neither analog affected blood levels of PRL, TSH, LH, FSH, ACTH, insulin, glucagon, glucose, cortisol, free thyroxine, and free triiodothyronine. No side effects were noted other than transient flushing with the highest dose administered. The findings demonstrate GHRH(1–29)-NH 2 and its D-Ala 2 analog are potent stimulators of GH release and have potential application in clinical medicine.