Suppression and recovery of the neonatal hypothalamic-pituitary-adrenal axis after prolonged dexamethasone therapy

Ford, Lisa R.; Willi, Steven M.; Hollis, Bruce W.; Wright, Nancy A.

doi:10.1016/s0022-3476(97)70100-8

Cited by 45 publications

(38 citation statements)

References 18 publications

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“…Withdrawal of long-term corticosteroid treatment in both man (Graber et al 1965, Harrison et al 1982, Schlaghecke et al 1992, Ford et al 1997) and adrenalintact rats (Nicholson et al 1984, Calogero et al 1990, Huang 1994) has been shown to reduce temporarily the ability of each component of the hypothalamo-pituitaryadrenal (HPA) axis to respond to endogenous and exogenous stimuli. The rate of recovery of the individual components of the HPA axis vary and a number of factors influence restoration of appropriate responsiveness.…”

Section: Introductionmentioning

confidence: 99%

“…In man, the biochemical but not necessarily clinical recovery of the HPA axis following short courses of glucocorticoid treatment appears to be complete from between 5 and 10 days after each treatment (Carella et al 1993). Chronic alternate-day glucocorticoid therapy results in relatively mild suppression of the HPA axis (Schurmeyer et al 1985) but prolonged exposure at high levels, either through administration of pharmacological doses for immunosuppressive or anti-inflammatory effects, or endogenous supraphysiological levels in Cushing's disease, may cause HPA axis suppression lasting a year or more (Graber et al 1965, Livanou et al 1967, Harrison et al 1982, Avgerinos et al 1987, Schlaghecke et al 1992, Ford et al 1997. In intact male rats treated with dexamethasone for between 2 and 14 days, it has been shown that recovery of pituitary corticotrophs in terms of adrenocorticotrophin (ACTH) secretion occurs between 4 and 7 days after withdrawal of the glucocorticoid (Nicholson et al 1984, Calogero et al 1990, Huang 1994.…”

Section: Introductionmentioning

confidence: 99%

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Anterior pituitary trophic responses to dexamethasone withdrawal and repeated dexamethasone exposures

Nolan

Levy²

2001

Journal of Endocrinology

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Glucocorticoid withdrawal, depending on the dose and duration of treatment, results in a transient but sometimes prolonged reduction in hypothalamo-pituitary-adrenal (HPA) axis secretory responsiveness. As the anatomic basis of HPA axis suppression remains uncertain, we have directly examined changes in trophic activity within the rat anterior pituitary gland following dexamethasone withdrawal and re-treatment. Treatment of adrenalectomised, male Wistar rats with dexamethasone results in a discrete, highly significant burst of apoptosis in the anterior pituitary with concurrent suppression of mitosis. Despite a surge in mitotic activity immediately after dexamethasone withdrawal, calculated total anterior pituitary cell populations remain below that seen in untreated adrenalectomised controls. Repeated exposures to dexamethasone show that the dexamethasone-sensitive cell population that is deleted by apoptosis is partially but not completely restored. As the amplitude of apoptotic bursts induced by second and third dexamethasone exposures are similar but smaller than that induced by initial exposure, it appears that the very first exposure to dexamethasone deletes a subset of anterior pituitary cells that are either not restored at all, or are only replaced very slowly. The reduced proportion of corticotrophs contributing to the increase in mitotic index after dexamethasone withdrawal corroborates this. Although continued cell turnover within the pituitary predicts that the absolute cellular deficit would diminish with time, the effects seen may contribute to the delayed recovery of pituitary axis function following cessation of glucocorticoid treatment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Anterior pituitary trophic responses to dexamethasone withdrawal and repeated dexamethasone exposures

Nolan

Levy²

2001

Journal of Endocrinology

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“…A major motivation for this therapy is the promotion of surfactant production and lung maturation and to induce closure of the ductus arteriosus (6,34,43,45,47). Dexamethasone decreases the duration of ventilatory support and lowers the incidence of chronic lung disease (13,23,33,50).Dexamethasone therapy, however, may lead to unfavorable long-term sequelae, including decreases in neuromotor and cognitive function (4,15,30,36,37,55), and may also lead to left ventricular abnormalities and metabolic dysfunction (5,14,17,24). A report of lipid intolerance in infants treated with dexamethasone highlights this potential for long-term metabolic dysfunction (2).…”

mentioning

confidence: 99%

“…Dexamethasone therapy, however, may lead to unfavorable long-term sequelae, including decreases in neuromotor and cognitive function (4,15,30,36,37,55), and may also lead to left ventricular abnormalities and metabolic dysfunction (5,14,17,24). A report of lipid intolerance in infants treated with dexamethasone highlights this potential for long-term metabolic dysfunction (2).…”

mentioning

confidence: 99%

Dexamethasone treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids

Bruder

Lee²,

Raff³

2005

Journal of Applied Physiology

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treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids. J Appl Physiol 98: [981][982][983][984][985][986][987][988][989][990] 2005. First published November 12, 2004; doi:10.1152/japplphysiol.01029.2004.-Dexamethasone is used as treatment for a variety of neonatal syndromes, including respiratory distress. The present study utilized the power of comprehensive lipid profiling to characterize changes in lipid metabolism in the neonatal lung and brain associated with dexamethasone treatment and also determined the interaction of dexamethasone with hypoxia. A 4-day tapering-dose regimen of dexamethasone was administered at 0800 on postnatal days 3 (0.5 mg/kg), 4 (0.25 mg/kg), 5 (0.125 mg/kg), and 6 (0.05 mg/kg). A subgroup of rats was exposed to hypoxia from birth to 7 days of age. Dexamethasone treatment elicited numerous specific changes in the lipid profile of the normoxic lung, such as increased concentrations of saturated fatty acids in the phosphatidylcholine and cholesterol ester classes. These increases were more profound in the lungs of hypoxic pups. Additional increases in cardiolipin concentrations were also measured in lungs of hypoxic pups treated with dexamethasone. We measured widespread increases in serum lipids after dexamethasone treatment, but the effects were not equivalent between normoxic and hypoxic pups. Dexamethasone treatment in hypoxic pups increased 20:4n6 and 22:6n3 concentrations in the free fatty acid class of the brain. Our results suggest that dexamethasone treatment in neonates elicits specific changes in lung lipid metabolism associated with surfactant production, independent of changes in serum lipids. These findings illustrate the benefits of dexamethasone on lung function but also raise the potential for negative effects due to hyperlipidemia and subtle changes in brain lipid metabolism. hypoxia; glucocorticoid therapy; neonate INHALED AND SYSTEMIC GLUCOCORTICOIDS have been widely used to treat syndromes of perinatal distress, many of which have an inflammatory component requiring pharmacological therapy (3,7,23,25,53). Dexamethasone, a highly potent glucocorticoid, has been the treatment of choice for neonates who are hypoxic due to cardiopulmonary conditions such as bronchopulmonary dysplasia (2,13,33,46,50). A major motivation for this therapy is the promotion of surfactant production and lung maturation and to induce closure of the ductus arteriosus (6,34,43,45,47). Dexamethasone decreases the duration of ventilatory support and lowers the incidence of chronic lung disease (13,23,33,50).Dexamethasone therapy, however, may lead to unfavorable long-term sequelae, including decreases in neuromotor and cognitive function (4,15,30,36,37,55), and may also lead to left ventricular abnormalities and metabolic dysfunction (5,14,17,24). A report of lipid intolerance in infants treated with dexamethasone highlights this potential for long-term metabolic dysfunction (2). It is for these reasons that the use of dexamethasone in neonates is decreasing (39) and...

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“…Basal cortisol levels in the 400-g/d beclomethasone group were similar to those reported in historical controls of other studies evaluating the hypothalamic-pituitary-adrenal axis in VLBW infants who had received either placebo or inhaled steroids. 18,19 Basal cortisol levels in the 800-g/d beclomethasone group were significantly lower than the 400-g/d beclomethasone group. In the intravenous dexamethasone group, basal cortisol levels were even lower than either inhaled group but similar to levels previously reported.…”

Section: Discussionmentioning

confidence: 85%

A Randomized Trial of Inhaled Versus Intravenous Steroids in Ventilator-Dependent Preterm Infants

Suchomski

Cummings

2002

J Perinatol

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Suppression and recovery of the neonatal hypothalamic-pituitary-adrenal axis after prolonged dexamethasone therapy

Cited by 45 publications

References 18 publications

Anterior pituitary trophic responses to dexamethasone withdrawal and repeated dexamethasone exposures

Anterior pituitary trophic responses to dexamethasone withdrawal and repeated dexamethasone exposures

Dexamethasone treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids

A Randomized Trial of Inhaled Versus Intravenous Steroids in Ventilator-Dependent Preterm Infants

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