Effects of Late Gestational Fetal Exposure to Dexamethasone Administration on the Postnatal Hypothalamus-Pituitary-Adrenal Axis Response to Hypoglycemia in Pigs

Abstract

Background: Prenatal glucocorticoid administration alters the activity of the fetal hypothalamic-pituitary-adrenocortical axis (HPAA), and correspondingly the adenocorticotropic hormone (ACTH) and cortisol levels after birth. The dosages required for these effects are critically discussed. Activation of the HPAA is related to metabolic syndrome and diabetes mellitus. Hypoglycemia is the classic side effect of antidiabetic treatment. We hypothesized that a low dosage of dexamethasone in late pregnancy alters the HPAA response to hypoglycemia in pigs. Methods: 12 pregnant sows were randomly assigned to two groups which received either a low-dose intramuscular injection (99th and 100th day of gestation) of dexamethasone (0.06 μg/kg body weight) or vehicle. Three months after birth, 18 dexamethasone-treated anaesthetized offspring and 12 control offspring underwent a 75 min hypoglycemic clamp (blood glucose below 4 mmol/L) procedure. Heart rate (HR), blood pressure, ACTH and cortisol levels and body weight (at birth and after three months) were recorded. Results: Dexamethasone-treated animals exhibited significantly elevated ACTH (139.9 ± 12.7 pg/mL) and cortisol (483.1 ± 30.3 nmol/L) levels during hypoglycemia as compared to the control group (41.7 ± 6.5 pg/mL and 257.9 ± 26.7 nmol/L, respectively), as well as an elevated HR (205.5 ± 5.7 bpm) and blood pressure (systolic: 128.6 ± 1.5, diastolic: 85.7 ± 0.7 mmHg) response as compared to the control group (153.2 ± 4.5 bpm; systolic: 118.6 ± 1.6, diastolic: 79.5 ± 1.4 mmHg, respectively; p < 0.001). Conclusions: Low-dose prenatal administration of dexamethasone not only exerts effects on the HPAA (ACTH and cortisol concentration) and vital parameters (HR and diastolic blood pressure) under baseline conditions, but also on ACTH, HR and systolic blood pressure during hypoglycemia.

Underlying mechanism of subcortical brain protection during hypoxia and reoxygenation in a sheep model - Influence of α1-adrenergic signalling

“…CBF was recorded at a sample rate of 40/s with a laser Doppler flowmeter (DRT4, Moor, Devon, UK). After the experiment animals were euthanized by intravenous injection of pentobarbital sodium (Narcoren, Merial, Halbergmoos, Germany) as described previously [ 26 , 27 ].…”

Role of the Hypothalamic–Pituitary–Adrenal Axis in Health and Disease

“…The authors correlated the dampened stress response of the HPA axis in the presence of their pups in lactating rats to the high levels of circulating prolactin levels and increased prolactin receptor expression in the central nervous system and the restoration of the stress response to pre-pregnancy levels occurred once prolactin and prolactin receptor levels returned to their pre-pregnancy state. The second article by Schiffner et al [ 3 ] hypothesizes that prenatal maternal exposure to low doses of the synthetic glucocorticoid dexamethasone may cause an alteration of the counter regulatory response of endogenous ACTH and cortisol during hypoglycemia. This hypothesis is based on the observations that stress hormones, such as ACTH and cortisol, stimulate gluconeogenesis and glucose release, that the activation of the HPA axis is related to metabolic syndrome and diabetes mellitus, and that hypoglycemia, with a resulting increase in ACTH and cortisol as a counter-regulatory response, is a common side effect of anti-diabetic treatment.…”

Renal Glucose Release after Unilateral Renal Denervation during a Hypoglycemic Clamp in Pigs with an Altered Hypothalamic Pituitary Adrenal Axis after Late-Gestational Dexamethasone Injection

“…Hypoglycaemia is one of the most common and dangerous side-effects of anti-diabetic treatment. In previous experiments, we were able to demonstrate that exposure to late-term GC causes elevated concentrations of ACTH and cortisol both at baseline and during hypoglycaemia in pigs as compared to control animals [ 25 ]. Moreover, in a different study, we showed that in pigs with unilateral renal denervation, the renal glucose release of the ablated kidney during conditions of severe hypoglycaemia was significantly diminished compared to that of the non-ablated organ.…”