Metabolism of Dexamethasone: Sites and Activity in Mammalian Tissues

Siebe, H.; Baude, G; Lichtenstein, I.; Wang, D; Bühler, H.; Hoyer, G.‐A.; Hierholzer, Klaus

doi:10.1159/000173753

Cited by 31 publications

(27 citation statements)

References 22 publications

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“…Both dexamethasone and cortisol are able to cross the placenta in rats (8,40,46,58) and sheep (16,17,35) and lead to adverse outcomes for adult offspring, but the extent to which each glucocorticoid actually crosses the placenta into the fetal circulation and accesses fetal tissues in early gestation is unknown. Dexamethasone is poorly metabolized by 11␤-HSD-2 and, therefore, most readily crosses the placenta (11,59). Therefore, it seemed likely that the placenta and fetal tissues would have a greater glucocorticoid exposure following dexamethasone compared with cortisol in the present study.…”

Section: Discussionmentioning

confidence: 84%

Maternal exposure to dexamethasone or cortisol in early pregnancy differentially alters insulin secretion and glucose homeostasis in adult male sheep offspring

Blasio¹,

Dodic²,

Jefferies³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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An adverse intrauterine environment increases the risk of developing various adult-onset diseases, whose nature varies with the timing of exposure. Maternal undernutrition in humans can increase adiposity, and the risk of coronary heart disease and impaired glucose tolerance in adult life, which may be partly mediated by maternal or fetal endocrine stress responses. In sheep, dexamethasone in early pregnancy impairs cardiovascular function, but not glucose homeostasis in adult female offspring. However, male offspring are often more susceptible to early life “programming”. Pregnant sheep were infused intravenously with saline (0.19 ml/h), dexamethasone (0.48 mg/h), or cortisol (5 mg/h), for 2 days from 26 to 28 days of gestation. In male offspring, size at birth and postnatal growth were measured, and glucose tolerance [intravenous glucose tolerance test (IVGTT)], insulin secretion, and insulin sensitivity of glucose, α-amino nitrogen, and free fatty acid metabolism were assessed at 4 yr of age. We show that cortisol, but not dexamethasone, treatment of mothers causes fasting hyperglycemia in adult male offspring. Maternal cortisol induced a second-phase hyperinsulinemia during IVGTT, whereas maternal dexamethasone induced a first-phase hyperinsulinemia. Dexamethasone improved glucose tolerance, while cortisol had no impact, and neither affected insulin sensitivity. This suggests that maternal glucocorticoid exposure in early pregnancy alters glucose homeostasis and induces hyperinsulinemia in adult male offspring, but in a glucocorticoid-specific manner. These consequences of glucocorticoid exposure in early pregnancy may lead to pancreatic exhaustion and diabetes longer term and are consistent with stress during early pregnancy contributing to such outcomes in humans.

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Section: Discussionmentioning

confidence: 84%

Maternal exposure to dexamethasone or cortisol in early pregnancy differentially alters insulin secretion and glucose homeostasis in adult male sheep offspring

Blasio¹,

Dodic²,

Jefferies³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…These patterns are also evident when low dexamethasone doses are administered (14). The activity of the 11␤-hydroxysteroid dehydrogenase type 1 and 2, which catalyze not only the reversible interconversion of cortisol to cortisone (34) but also that of dexamethasone to 11-dehydrodexamethasone (35,36) may explain the difference between the sexes. Previous studies have shown that obesity and gender may have different effects on 11␤-hydroxysteroid dehydrogenase activity and, consequently, on cortisol concentrations (37,38) and HPA axis responsiveness to CRH and AVP (8).…”

Section: Discussionmentioning

confidence: 99%

Cortisol and ACTH Response to Oral Dexamethasone in Obesity and Effects of Sex, Body Fat Distribution, and Dexamethasone Concentrations: A Dose-Response Study

Pasquali

Ambrosi

Armanini

et al. 2002

The Journal of Clinical Endocrinology & Metabolism

107

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There is increasing evidence that the abdominal obesity phenotype may be associated with multiple alterations of the hypothalamic-pituitary-adrenocortical (HPA) axis activity in both sexes. Our hypothesis is that the lack of adequate cortisol suppression after the dexamethasone test may constitute an indirect marker of HPA axis hyperactivity in the presence of the abdominal obesity phenotype. A total of 34 normal-weight (13 men and 21 women) and 87 obese (36 men and 51 women), healthy, nondepressed subjects therefore underwent four different dexamethasone suppression tests randomly performed at varying intervals of at least 1 wk between each test. After a standard overnight 1-mg dexamethasone test, which served as a reference, three other tests were randomly performed at 1-wk intervals by administering 0.0035, 0.0070, and 0.015 mg oral dexamethasone per kilogram of body weight overnight. Blood samples were obtained for cortisol, ACTH, and dexamethasone. Results were analyzed separately in men and women as well as in normal-weight [body mass index (BMI) <25 kg/m 2 ] and overweight or obese (BMI >25 kg/m 2 ) subjects. The waist circumference and the waist to hip ratio (WHR) were used as markers of body fat distribution. After the standard 1-mg test, cortisol suppression was greater than 90% in all subjects. However, after each test, obese women had significantly higher values of percent cortisol and percent ACTH suppression than normal-weight women without any difference between obese and normal-weight men. Considering the response to the three variable-dose tests, a clear doseresponse pattern (P < 0.001 for trend analysis) in percent cortisol and percent ACTH suppression was found in all subjects. After each test men had significantly higher dexamethasone levels than women, regardless of BMI. However, obese women, but not men, had significantly higher dexamethasone levels after each test than their normal-weight counterpart. Plasma dexamethasone concentrations were dose related (P < 0.001 for trend analysis) in all subjects, but the doserelated increase was significantly higher in normal-weight men than normal-weight women, whereas it was similar in obese subjects of both sexes. Stepwise multiple regression analysis revealed that both percent cortisol and percent ACTH variations were significantly and negatively influenced by dexamethasone levels, as well as by waist circumference values in men, and independently by BMI and waist circumference in women. However, in contrast to what has been found in men, a divergent contribution of BMI and waist circumference was found in women indicating that, with increasing waist values, a smaller suppression of the HPA axis was found with respect to that expected on the basis of BMI values. In conclusion, this study provides data of both physiological and physiopathological relevance. Overall, our data indicated that adjustment of the dexamethasone dose to body weight does not seem to substantially improve the sensitivity of the test, even in obese individuals, particularly w...

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“…Dies ist von erheblicher Relevanz, da derzeit fast 10% aller Schwangeren im letzten Drittel der Schwangerschaft mit synthetischen Glukokortikoiden aufgrund einer vermeintlichen oder tatsächlichen Gefahr einer Früh-geburt behandelt werden. Synthetische Glukokortikoide wie Betamethason und Dexamethason sind potenziell besonders effektiv bei der akuten Veränderung des Funktionszustandes des fetalen Gehirns und der Programmierung affektiver Störungen und neuropsychologischer Auffälligkeiten im späteren Leben, da das plazentare Enzym 11 ␤ -HSD2, das den Übertritt von Glukokortikoiden in die fetale Zirkulation reguliert, nur eine niedrige Affinität zu synthetischen Glukokortikoiden hat, sodass diese nahezu ungehindert in die fetale Zirkulation überge-hen [113][114][115] . Tatsächlich hat bereits eine einmalige prä-natale Glukokortikoidbehandlung akute und chronische Effekte auf die Hirnfunktion.…”

Section: Akute Effekte Einer Pränatalen Glukokortikoidtherapieunclassified

Intrauterine Programmierung von Störungen der Hirnfunktion im späteren Leben

Schwab¹

2009

Gynäkol Geburtshilfliche Rundsch

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Die Entwicklung der Hirnfunktion wird pränatal durch epigenetische Faktoren, die insbesondere mit einer fetalen Mangelversorgung oder erhöhten fetalen Stresshormonkonzentrationen einhergehen, beeinflusst. Schon eine moderate Mangelernährung hat Effekte auf die Hirnentwicklung u.a. über eine Hemmung des Systems des insulinähnlichen Wachstumsfaktors. Daneben führt sie zu einer Erhöhung von mütterlichen Kortisolkonzentrationen im fetalen Kreislauf. Erhöhte fetale Kortisolkonzentrationen, sei es aufgrund fetaler Mangelversorgung, Stress oder pränataler Gabe von Glukokortikoiden, führen ebenfalls zu Störungen der Hirnentwicklung. Darüber hinaus induzieren sie in den letzten Wochen der Schwangerschaft, wenn die kindliche Hypophysen-Hypothalamus-Nebennieren-(HHN)-Achse reift, eine dauerhafte Desensitivierung von Glukokortikoidrezeptoren im Hippokampus. Diese bewirkt eine verminderte negative Rückkopplung der HHN-Achse mit der Folge einer verstärkten Kortisolausschüttung und einer erhöhten Stressempfindlichkeit im späteren Leben. Die Störungen der Hirnentwicklung und die dauerhaft erhöhten Kortisolspiegel induzieren subtile kognitive Störungen, Verhaltensauffälligkeiten und eine Prädisposition für depressive und schizophrene Erkrankungen.

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Metabolism of Dexamethasone: Sites and Activity in Mammalian Tissues

Cited by 31 publications

References 22 publications

Maternal exposure to dexamethasone or cortisol in early pregnancy differentially alters insulin secretion and glucose homeostasis in adult male sheep offspring

Maternal exposure to dexamethasone or cortisol in early pregnancy differentially alters insulin secretion and glucose homeostasis in adult male sheep offspring

Cortisol and ACTH Response to Oral Dexamethasone in Obesity and Effects of Sex, Body Fat Distribution, and Dexamethasone Concentrations: A Dose-Response Study

Intrauterine Programmierung von Störungen der Hirnfunktion im späteren Leben

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