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Abuse of recombinant human growth hormone: studies in two different dog models
No full textThe search for inappropriately high growth hormone (GH) titers in plasma has been widely used to detect GH abuse, despite many shortcomings especially related to the pulsatile nature of GH secretion. Hence, the need for new anti-doping strategies. In the present study dogs were used to evaluate the ability of recombinant human GH (rhGH) to affect canine GH (cGH) release ensuing after somatostatin (SS) infusion withdrawal (SSIW) - a purported stimulus for the release of endogenous GHreleasing hormone (GHRH) - or the cGH response to administration of a GH-releasing peptide (GHRP). In the SSIW experiments, 8 beagle dogs of either gender (4-6 years old) were given a subcutaneous bolus injection of physiological saline (0.1 ml/kg) or, alternatively, rhGH (0.2 IU/kg s.c.) 60 min before the starting a continuous infusion of SS (4 μg/kg g h i.v.) of 1.5 h duration. In the dogs given a saline bolus, SSIW was followed by a 'rebound' rise in plasma cGH levels. In contrast, in dogs which had received the bolus injection of rhGH, the cGH rise elicited by SSIW was completely abrogated. In the set of experiments with a GHRP challenge, 13 dogs of either gender (3-12 years old) received the following treatment schedule at least 15 days apart: (1) a single bolus injection of rhGH (0.2 IU/kg s.c.); (2) rhGH (0.05 IU/ kg s.c.) daily for 12 days; (3) rhGH (0.2 IU/kg s.c.) on alternate days for 12 days, and (4) rhGH (0.2 IU/kg s.c.) daily for 12 days. For each treatment schedule, before treatment, during treatment (24 h from the previous rhGH injection) and 1, 5 and 10 days after treatment, all dogs received an intravenous injection of a GHRP, EP51216 (125 μg/kg). In all treatments under baseline conditions, a single injection of EP51216 elicited an abrupt rise in plasma cGH. Twenty-four hours after the injection of an acute bolus of rhGH, the C max and AUC 0-90 of the GHRP-stimulated cGH response were significantly lower than the baseline cGH response. Five days later, there was a trend in the C max and AUC 0-90 towards complete restoration of the original values. One, 5 and 10 days after the end of the daily treatment with rhGH (0.05 IU/kg s.c.), no significant changes in the GHRP-stimulated cGH responses vs. the baseline GH response were recorded. In contrast, treatment with rhGH at a dose of 0.2 IU/kg s.c., on either alternate or daily administration, markedly reduced the GHRP-stimulated cGH responses evaluated after 3 and 5 rhGH injections. One day after the last rhGH injection, the EP51216-stimulated cGH response was still significantly reduced when compared with that present under baseline conditions. Five and 10 days following termination of rhGH treatment on alternate days, no significant differences in the C max and AUC 0-90 of the cGH responses to EP51216 were present. Differently, following the end of daily rhGH treatment, a marked inhibition in the C max of the cGH response to EP51216 was still present at 1 and 5 days, though not at 10 days. In conclusion, these studies show that a single administration of rhGH can abrogate the cGH response ensuing SSIW or acute stimulation by a GHRP. The inhibitory effect of rhGH on the cGH response to GHRP is present even 5 days after termination of a short-lived treatment with rhGH at a dose (0.2 IU/kg) which, in the dog, is undoubtedly lower than that used in humans for doping purposes. Extrapolation of these preclinical results to humans may pave the way for the development of a new rhGH anti-doping test. Copyrigh
The leukocyte expression of CD36 is reduced in patients with Alzheimer disease and in early phase of dementia
No full textLa transizione menopausale : un milieu biologico-endocrino che predispone alla neurodegenerazione
No full textTestosterone inhibition of growth hormone release stimulated by a growth hormone secretagogue : studies in the rat and dog
No full textAnabolic 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 × 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 μg/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 μg/kg/day s.c.; rhGH, 400 μg/kg/day s.c.; 0.9% saline 0.1 ml/kg/day s.c.; ×11 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, Cmax and AUC0-90 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 downregulation of hypothalamic GHS-R
Muscolar expression of MGF, IGF-1Ea and myostatin in intact and hypofysectomized rats : effects of rhGH and testosterone alone or combined
No full textMuscle expressions of MGF, IGF-IEa and myostatin in intact and hypophysectomized rats : effects of rhGH and testosterone alone or combined
No full textMyostatin and mechano-growth factor (MGF), an isoform of insulin-like growth factor-I (IGF-I), are two important regulators of muscle hypertrophy. The aim of the present study was to investigate the effects of recombinant human growth hormone (rhGH) and/or testosterone on muscle MGF/IGF-IEa/myostatin expression in intact and hypophysectomized rats treated for 15 d with 1) saline or rhGH, 2) sesame oil or testosterone, 3) saline+sesame oil, or rhGH+testosterone (first experiment) or for 7 d with saline or rhGH (second experiment). Animals were killed by decapitation 24 h or 4 d after the last injection (first or second experiment, respectively). Muscle expressions of MGF, IGF-IEa, and myostatin were determined by RT-PCR. A significant increase in the weight of gastrocnemius muscle was observed only in hypophysectomized rats treated with rhGH alone or in combination with testosterone. Administration of rhGH to hypophysectomized rats caused a marked increase in both MGF and IGF-IEa muscle mRNA levels (without any change in the muscle expression of myostatin), an effect that was abolished when testosterone was combined with rhGH. Conversely, in intact rats rhGH increased myostatin muscle mRNA levels without affecting those of MGF and IGF-IEa. Testosterone, alone or combined with rhGH, induced an inhibition of myostatin expression in the muscle of intact rats, but did not change muscle paradigms of hypophysectomized rats. In conclusion, rhGH and/or testosterone anabolic effects in the muscle are mediated by a different expression of MGF/IGF-IEa/myostatin, which is related to the pituitary function
The leukocyte expression of CD36 is low in patients with Alzheimer's disease and mild cognitive impairment
No full textCD36, a scavenger receptor of class B (SR-B), helps mediate microglial and macrophage response to beta-amyloid fibrils (betaA), and seems to play a key role in the proinflammatory events associated with Alzheimer disease (AD) in many tissues. Peripheral leukocytes express many molecules and multiple receptors which undergo the same regulatory mechanisms as those operative in the brain. Thus, these cells, easily obtainable through peripheral blood sampling, may be used as a tool to investigate changes occurring in inaccessible brain areas. Based on these premises, we investigated the leukocyte expression of CD36 in 70 AD patients and in 30 subjects with mild cognitive impairment (MCI). Results were compared to those of 20 young and 40 age-matched control subjects. Leukocyte expression of CD36 was significantly reduced versus controls in both AD and MCI patients, while in young and old controls there were no age-related changes. Although preliminary, these data indicate that the reduction of CD36 expression in leukocytes is a disease-related phenomenon, occurring since the early stages of AD (MCI). Irrespective of the mechanism(s) underlying such changes, assessment of leukocyte CD36 expression might represent an useful tool to support the diagnosis of AD and to screen MCI patients candidates to develop the disease
The Leukocyte Expression of CD36 and other Biomarkers: Risk Indicators of Alzheimer’s Disease
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