Elements in the pathophysiology of diminished growth hormone (GH) secretion in aging humans

Veldhuis, Johannes D.; Iranmanesh, Ali; Weltman, Arthur

doi:10.1007/bf02778061

Cited by 93 publications

(22 citation statements)

References 74 publications

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“…It has recently been reported that, in transgenic GHRH-green fluorescent protein mice, aging does not decrease GHRH but causes an enlargement of GHRH-positive axons suggestive of neuropeptide accumulation (2). It has been suggested, and confirmed in our laboratory, that GHRH-receptor (GHRH-R) mRNA levels in the pituitary decline with age (24), which is in agreement with the age-related decline of pituitary GHRH sensitivity, although there is no general consensus on this point (10,50,61). Because GHRH-R is upregulated by the hypothalamic GHRH (21), our previous findings suggest that a major event in the decline of GH might be the decrease of hypothalamic GHRH secretion.…”

supporting

confidence: 75%

Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis

Frutos¹,

Cacicedo²,

Fernández³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Growth hormone (GH) secretion and serum insulin-like growth factor-I (IGF-I) decline with aging. This study addresses the role played by the hypothalamic regulators in the aging GH decline and investigates the mechanisms through which growth hormone secretagogues (GHS) activate GH secretion in the aging rats. Two groups of male Wistar rats were studied: young-adult (3 mo) and old (24 mo). Hypothalamic growth hormone-releasing hormone (GHRH) mRNA and immunoreactive (IR) GHRH dramatically decreased (P Ͻ 0.01 and P Ͻ 0.001) in the old rats, as did median eminence IR-GHRH. Decreases of hypothalamic IR-somatostatin (SS; P Ͻ 0.001) and SS mRNA (P Ͻ 0.01), and median eminence IR-SS were found in old rats as were GHS receptor and IGF-I mRNA (P Ͻ 0.01 and P Ͻ 0.05). Hypothalamic IGF-I receptor mRNA and protein were unmodified. Both young and old pituitary cells, cultured alone or cocultured with fetal hypothalamic cells, responded to ghrelin. Only in the presence of fetal hypothalamic cells did ghrelin elevate the age-related decrease of GH secretion to within normal adult range. In old rats, growth hormone-releasing peptide-6 returned the levels of GH and IGF-I secretion and liver IGF-I mRNA, and partially restored the lower pituitary IR-GH and GH mRNA levels to those of young untreated rats. These results suggest that the aging GH decline may result from decreased GHRH function rather than from increased SS action. The reduction of hypothalamic GHS-R gene expression might impair the action of ghrelin on GH release. The role of IGF-I is not altered. The aging GH/IGF-I axis decline could be rejuvenated by GHS treatment. growth hormone; ghrelin; growth hormone-releasing peptide-6; growth hormone secretagogue; aging; growth hormone decline GROWTH HORMONE (GH) secretion in humans and rats declines progressively with aging (17, 41) and results in lower serum insulin-like growth factor-I (IGF-I) levels.Early studies in elderly humans showed an age-associated attenuation of GH pulse amplitude and GH secretion in response to several stimuli, including insulin-induced hypoglycemia and arginine administration (32,43). Subsequent studies revealed a decrease in plasma IGF-I parallel to the decline in GH pulses (51). The studies in humans have been confirmed in experimental animals, and it is now evident that the decline in high-amplitude pulsatile GH release and plasma IGF-I concentrations is one of the best characterized events that occur with aging in humans and rats (61). Thus the aging rat is a model of relative or partial GH deficiency and consequently is suitable for studying the mechanisms of this alteration.GH has a broad range of actions and therefore its diminished secretion rate has clinical significance and may be responsible for the generalized catabolic state, functional alterations, cognitive impairment, and decreased neuroprotection associated with normal aging. In elderly adults, with or without GH defect, GH increases IGF-I, the lean-to-fat ratio, muscle strength, and skin thickness and reduces total body fat cont...

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supporting

confidence: 75%

Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis

Frutos¹,

Cacicedo²,

Fernández³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…These findings suggest a disruption of the GH-IGF1 axis activity based on a change in regular sleep pattern with this disease (54), or that this could be an effect of the small sample size. Although 1 month of sham ventilation induced elevated IGF1 levels (55), normalization of sleep pattern induced a restoration of the GH axis activity.…”

Section: Discussionmentioning

confidence: 82%

Effects of long-term continuous positive airway pressure on body composition and IGF1

Münzer

Hegglin

Stannek

et al. 2010

European Journal of Endocrinology

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Objective: To investigate the long-term effects of nasal continuous positive airway pressure (CPAP) ventilation in patients with obstructive sleep apnea syndrome (OSAS) on body composition (BC) and IGF1. Design: Observational study. Subjects: Seventy-eight (11 females and 67 males) OSAS patients who were compliant with CPAP (age 51G1.1 years) participated in the study. We assessed body mass index (BMI), total body mass (TBM), total body fat (TBF; kg) and lean body mass (LBM; kg), abdominal subcutaneous (SC) and visceral (V) fat (cm 2 ), and waist circumference (WC; cm) by magnetic resonance imaging, and IGF1 (ng/ml) before and after 7.8G1.3 months of CPAP use of an average of 5.9G1.2 h. Results: Women had a higher BMI, WC; TBM, TBF, and more SC fat. Men had a higher LBM and more V fat. CPAP increased WC (C2.8G9.6 cm, PZ0.02) and LBM (2.2G0.5 kg, PZ0.006), but not IGF1. In men, CPAP increased BMI (0.5G0.2 kg/m 2 , PZ0.02), WC (1.7G6.9 cm, PZ0.002), TBM (1.7G0.4 kg, PZ0.0001), LBM (1.5G0.4 kg, PZ0.0003), SC fat (12.9G5.1 cm 2 , PZ0.02), and IGF1 (13.6G4.2 ng/ml, PZ0.002). Compliance with CPAP increased LBM in men aged !60 years, but not in those aged O60 years, and IGF1 increased in men aged 40-60 years only. Conclusions: Long-term CPAP increased LBM in both sexes and IGF1 in men, while fat mass remained unchanged, suggesting a sexually dimorphic response of IGF1 to CPAP. The role of the GH axis activity and age to this response is unclear. The metabolic consequences of changes in LBM are still to be determined. Future studies on the effects of CPAP on BC should include LBM as an outcome.

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“…It exerts direct effect on protein and on carbohydrate and lipid metabolism, and controls the rate of skeletal and visceral growth (Salomon et al, 1996;Tsoshima T, 1998; Russell-Jones and Umpleby 1999). For reasons not yet fully understood, GH secretion gradually declines during normal aging (Corpas et al, 1993;Veldhuis et al, 1997). This decline with age reflects changes in both frequency and magnitude of secretory pulses.…”

Section: Introductionmentioning

confidence: 99%

METABOLISM, PHARMACOKINETICS, TISSUE DISTRIBUTION, AND EXCRETION OF [¹⁴C]CP-424391 IN RATS

Khojasteh-Bakht¹,

O’Donnell²,

Fouda³

et al. 2004

Drug Metab Dispos

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ABSTRACT:CP-424391, 2-amino-N-[3aR-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-benzyloxymethyl-2-oxoethyl]-isobutyramide, is an orally active growth hormone secretagogue currently being developed. In this study, we investigated the metabolic fate and disposition of radiolabeled CP-424391 in rats. Following 15 mg/kg single oral administration to Sprague-Dawley rats, 91% of the radiolabeled dose was recovered. Feces was the major route of excretion: 77% of the dose recovered in feces of the female rat and 84% in the male. Excretion in the urine was 15% in the female rat compared with 7% in the male. Both fecal and urinary metabolic profiles were consistent in both genders. The metabolic pathways of CP-424391 were oxidation at the benzyl group of the O-benzylserine moiety, N-demethylation of pyrazolidine, and/or Odebenzylation. In circulation, CP-424391 was absorbed within the first hour to an average apparent C max of 1.44 g/ml. CP-424391 accounts for about 40% of radioactivity area under the plasma concentrationtime curve and C max in circulation. The plasma terminal elimination half-life of CP-424391 was 2.4 h and for total radioactivity was 2.8 h. The radioactivity was widely distributed in all tissues except for the central nervous system. [ The growth hormone (GH) is a pulsatile hormone controlled in part by hypothalamus (Rizvi and Arslan, 1998). It exerts direct effect on protein and on carbohydrate and lipid metabolism, and controls the rate of skeletal and visceral growth (Salomon et al., 1996;Tsoshima T, 1998; Russell-Jones and Umpleby 1999). For reasons not yet fully understood, GH secretion gradually declines during normal aging (Corpas et al., 1993;Veldhuis et al., 1997). This decline with age reflects changes in both frequency and magnitude of secretory pulses. A spectrum of physiologic changes occur that are reminiscent of the adult GH deficiency syndrome (Jorgensen et al., 1994). The deleterious consequences of this deficiency include increased visceral adiposity, reduced lean body mass and muscle-to-fat ratio, osteopenia, fatigue and muscle weakness, reduced extracellular fluid volume, and decreased cardiac function. Although recombinant GH therapy represents the current standard of care for GH-deficient patients, it is not ideal due to adverse effects associated with long-term therapies (Gibney et al., 1999). On the other hand, GH secretagogue has shown marked improvements over the traditional remedies by enhancing pulse amplitudes and integrated hormone production in elderly subjects (Huhn et al., 1993;Aloi et al., 1994;Chapman et al., 1997).CP-424391 belongs to the pyrazolidine-piperidine class of compounds currently being developed as an orally active GH secretagogue for the treatment of growth hormone-compromised states. Its pharmacological mechanism of action is the elevation of circulating GH levels by stimulation of GH release from the pituitary gland (Pan, 2000). The objective of the present study was to investigate the metabolic fate and disposition of CP-...

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Elements in the pathophysiology of diminished growth hormone (GH) secretion in aging humans

Cited by 93 publications

References 74 publications

Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis

Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis

Effects of long-term continuous positive airway pressure on body composition and IGF1

METABOLISM, PHARMACOKINETICS, TISSUE DISTRIBUTION, AND EXCRETION OF [¹⁴C]CP-424391 IN RATS

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Elements in the pathophysiology of diminished growth hormone (GH) secretion in aging humans

Cited by 93 publications

References 74 publications

Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis

Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis

Effects of long-term continuous positive airway pressure on body composition and IGF1

METABOLISM, PHARMACOKINETICS, TISSUE DISTRIBUTION, AND EXCRETION OF [14C]CP-424391 IN RATS

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METABOLISM, PHARMACOKINETICS, TISSUE DISTRIBUTION, AND EXCRETION OF [¹⁴C]CP-424391 IN RATS