Testosterone inhibition of growth hormone release stimulated by a growth hormone secretagogue: studies in the rat and dog.
Anabolic steroids are frequently taken by athletes and bodybuilders together with recombinant human GH (rhGH), though there is some scientific evidence that the use of anabolic steroids reverses the rhGH-induced effects. Recently, we have shown that treatment with rhGH (0.2 IU/kg s.c., daily x 12 days) in the dog markedly reduced the canine GH (cGH) responses stimulated by EP51216, a GH secretagogue (GHS), evaluated after 3 and 5 daily rhGH injections, and that the inhibition was still present a few days after rhGH discontinuation. The aim of the present study was to evaluate in the dog the GH response to EP51216 (125 mug/kg i.v.) in a condition of enhanced androgenic function (i.e. acute injection or 15-day treatment with testosterone at the dose of 2 mg/kg i.m. on alternate days), and in the hypophysectomized rat the hypothalamic and hippocampal expression of ghrelin, the receptor of GHSs (GHS-R), GH-releasing hormone (GHRH) and somatostatin (SS) after specific hormonal replacement therapies (testosterone, 1 mg/kg/day s.c.; hydrocortisone, 500 mug/kg/day s.c.; rhGH, 400 mug/kg/day s.c.; 0.9% saline 0.1 ml/kg/day s.c.; x11 days). In the dog experiments, under baseline conditions, a single injection of EP51216 elicited an abrupt rise of plasma cGH. Twenty-four hours from the acute bolus injection of testosterone, C(max) and AUC(0-90) of the GHS-stimulated cGH response were significantly lower than baseline cGH response; 5 days later, there was still a significant decrease of either parameter versus the original values. Short-term treatment with testosterone markedly reduced the GHS-stimulated cGH responses evaluated during (5th bolus) and at the end (8th bolus) of testosterone treatment. Four and 8 days after testosterone withdrawal, the EP51216-stimulated cGH response was still significantly reduced when compared with that under baseline conditions. Plasma concentrations of insulin-like growth factor 1 (IGF-1) were stable until the 5th bolus of testosterone and decreased progressively in the remaining time of the testosterone treatment; 4 and 8 days from treatment withdrawal, IGF-1 levels were still suppressed. In rat studies, hypothalamic mRNA levels of GHS-R were significantly reduced by treatments with testosterone and hydrocortisone, whereas hippocampal expressions of ghrelin, GHRH and SS were reduced by rhGH replacement therapy. In conclusion, these studies show that a single administration of testosterone can abrogate the cGH response ensuing acute stimulation by a GHS; the inhibitory effect of testosterone on the cGH response to GHS is present during and even 8 days after termination of a short-lived treatment with testosterone; these events occur via a
Rigamonti
Antonello E
AE
Department of Medical Pharmacology, University of Milan, Milan, Italy.
Cella
Silvano G
SG
Giordani
Claudio
C
Bonomo
Sara M
SM
Giunta
Marialuisa
M
Sartorio
Alessandro
A
Muller
Eugenio
E
D045930:Anabolic Agents / Q000008:administration & dosage; D000818:Animals; D004285:Dogs; D054439:Ghrelin; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism*; D019382:Human Growth Hormone / Q000008:administration & dosage; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D036361:Peptide Hormones / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000378:metabolism; D011994:Recombinant Proteins; D013004:Somatostatin / Q000378:metabolism; D013739:Testosterone / Q000008:administration & dosage / Q000502:physiology*
D045930:Anabolic Agents; D054439:Ghrelin; D009842:Oligopeptides; D036361:Peptide Hormones; D017481:Receptors, Somatostatin; D011994:Recombinant Proteins; C420120:gamma-aminobutyryl-2-methyltryptophyl-2-methyltryptophyl-2-methyltryptophyl-lysinamide; D019382:Human Growth Hormone; D013739:Testosterone; D013004:Somatostatin; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone