Fat distribution was assessed by computed tomography in normal volunteers (n = 42), patients on long-term dialysis (n = 18), and patients on glucocorticoids [renal transplant patients (n = 49), other diseases (n = 17)]. Patients on glucocorticoids had higher mediastinal (deep) and identical or increased posterior cervical, buccal, and midthigh (superficial) fat areas when compared with normal subjects. The pattern of fat distribution in dialysis patients mimicked the distribution observed in patients taking glucocorticoids. Healthy females had higher ratios of superficial to deep fat than healthy male subjects. Patients on prednisone or on dialysis lost this sex-associated difference in fat distribution. Since patients on prednisone exhibit increased or normal thigh fat depots in the presence of increased mediastinal fat, the current concept that glucocorticoids induce redistribution of body fat from peripheral to central fat compartments has to be revised. Furthermore, disease states and/or glucocorticoids abrogate sex-associated differences in body fat distribution.
The effects of similar increases in total insulin-like growth factor I (IGF-I) plasma concentrations achieved by either recombinant human (rh) growth hormone (GH) or rhIGF-I administration on whole body protein and glucose kinetics were assessed. Twenty-six healthy subjects received methylprednisolone (0.5 mg.kg-1.day-1 orally) during 6 days in combination with either placebo (saline sc), GH (0.3 mg.kg-1.day-1 sc), or IGF-I (80 micrograms.kg-1.day-1 sc) in a double-blind randomized fashion. Glucocorticoid administration resulted in protein catabolism as indicated by an increase in leucine flux and a 62 +/- 13% increase in leucine oxidation ([1-13C]leucine infusion technique); this increase was abolished by GH (-1 +/- 18%) as was statistically insignificant during IGF-I treatment (+53 +/- 25%). GH increased endogenous glucose production by 28 +/- 8%, augmented glucocorticoid-induced insulin resistance of peripheral glucose clearance (euglycemic clamp), and increased circulating lipids. IGF-I administration resulted in both increased endogenous glucose production and increased peripheral glucose clearance such that plasma glucose concentrations remained unchanged by IGF-I. IGF-I lowered circulating GH and insulin and altered IGF binding proteins, which all may have reduced bioactivity of IGF-I. The data demonstrate that, in spite of similar total IGF-I plasma concentrations during treatment, GH and IGF-I exert markedly different effects on whole body leucine, glucose, and lipid metabolism.
The therapeutic response to and side effects of glucocorticoids will be better recognized and the recovery of the adrenals during the tapering of therapy with steroids better evaluated if endogenous and exogenous glucocorticoids are separately assessed. We describe a specific method for simultaneously measuring the concentrations of cortisone, cortisol, prednisone, and prednisolone in plasma by "high-pressure" liquid chromatography. The steroids, together with an internal standard, dexamethasone, are extracted from 1 mL of plasma with methylene chloride-ether, washed with acid and base, and separated isocratically on a normal-phase silica column with a mobile phase consisting of methylene chloride/tetrahydrofuran/methanol/glacial acetic acid (96.85/1/2.1/0.05 by vol) at a flow rate of 1.3 mL/min. The steroids are detected at 254 nm and quantitated by peak-height measurements; their retention times range from 6 to 20 min. The lower limits for routine detection of all four compounds is 10 microgram/L. The analytical recoveries are about 75%; the intra-day variability (CV) is 1 to 9%, and the inter-day variability 2 to 11%. Of 26 drugs and 20 steroids tested, only theophylline presents an interference problem.
The kinetics of prednisolone after intravenous prednisolone and oral prednisone were investigated in 19 young (23 to 34 years) and 12 elderly (65 to 89 years) subjects. The systemic availability of unbound prednisolone after oral prednisone and the apparent interconversion of prednisolone into prednisone and vice versa (reflecting the activity of the 11 beta-hydroxydehydrogenase) were independent of age. The total exposure of the elderly subjects to prednisolone was increased because the nonrenal (5.7 +/- 1.0 vs. 7.7 +/- 1.6 ml/min/kg, mean +/- SD; P less than 0.001) and renal (0.9 +/- 0.3 vs. 2.9 +/- 0.7 ml/min/kg; P less than 0.001) clearances of unbound prednisolone were lower in the elderly. The fractional clearance of 6 beta-hydroxyprednisolone (reflecting the activity of the 6 beta-hydroxylase) decreased linearly with the metabolic clearance of prednisolone. Despite increased prednisolone exposure, elderly subjects had higher endogenous cortisol concentrations. It was concluded that elderly subjects exhibit higher concentrations of both total and unbound prednisolone. Despite this greater exposure of target tissues, there appears to be less suppression of endogenous cortisol concentrations in plasma compared with younger subjects.
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