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.
Highlights
Endogenous gluconeogenesis is important for the maintenance of a stable blood glucose homeostasis in both humans and pigs [1]
Hypoglycemia was considered to be established at blood glucose concentrations below 4 mmol/L and was maintained for 75 min (Figure 1)
Baseline arterial blood glucose concentrations did not differ between both groups and were 8.1 ± 0.4 mmol/L in controls and 8.8 ± 0.4 mmol/L in the dexamethasone-treated group
Summary
Endogenous gluconeogenesis is important for the maintenance of a stable blood glucose homeostasis in both humans and pigs [1]. Previous studies have already provided solid evidence that prenatal maternal injection of synthetic glucocorticoids (GCs) [6,7,8], such as betamethasone and dexamethasone, induces changes in the activity of the hypothalamic-pituitary-adrenocortical axis (HPAA), which is responsible for the distribution of endogenous catecholamines. Changes in the HPAA have an influence on endogenous stress hormones like the adenocorticotropic hormone (ACTH) and cortisol, which stimulate glucose release [10,11], as well as on the autonomous nervous system, which is involved in gluconeogenesis [12,13]. We tested the hypothesis that a prenatal maternal low dosage injection of dexamethasone would cause an alteration of the counteregulatory responses of endogenous ACTH and cortisol during hypoglycemia in pigs. The experimental setup allows the experiment to be performed under deep general anesthesia
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