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CLAIRE-DOMINIQUE WALKER, SUSAN F. AKANA, CAREN S. CASCIO, MARY F. DALLMAN, Adrenalectomy in the Neonate: Adult-Like Adrenocortical System Responses to Both Removal and Replacement of Corticosterone, Endocrinology, Volume 127, Issue 2, 1 August 1990, Pages 832–842, https://doi.org/10.1210/endo-127-2-832
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Neonatal rats exhibit a period of diminished responsiveness to stress between days 3–10 of life, which has been shown to be associated with an increased sensitivity to corticosterone (B) inhibitory feedback. In this study we further investigated B feedback potency on regulation of ACTH by examining 1) the time course of changes in pituitary ACTH secretion and content, plasma B and B-binding globulin (CBG) concentrations, and thymus weight after adrenalectomy (ADX) performed on 5-day-old pups, with or without sc 5% B pellet replacement, and 2) the time required for acute (B injection) and the B dose required for constant (B pellet) inhibition of ACTH secretion in 10-day-old ADX neonates.
As in adult rats, ADX in neonates caused an immediate (3 h) large increase (13-fold) in plasma ACTH levels compared to that in sham-operated rats, followed by a decrease by 12 and 24 h after surgery and a further and sustained increase during the next 4 days. Pituitary ACTH stores were dimmished in ADX rats by 3, 12, and 24 h and increased thereafter. Five percent B pellet replacement abolished ADX-induced changes in plasma and pituitary ACTH until days 4–5, when plasma ACTH was slowly released from B inhibition (circulating B values were similar to ADX values). By day 10 of life, inhibition of plasma ACTH by calculated free B showed an IC50 of 1.09 nM. Plasma CBG concentrations exhibited a clear developmental pattern in sham-operated rats, being lower on days 6–8 than earlier or later. Typical ADX-induced increases in CBG levels were observed from day 3 on after surgery, at the same time as a transient decrease in CBG levels occurred in ADX plus 5% B rats. On day 10 of age, inhibition of CBG by calculated free B demonstrated an IC50 of 1.5 nM. Although no enlargement of the thymus was observed after neonatal ADX, thymus weight was significantly diminished by 12 h after B replacement and in a dose-related manner at 5 days with B pellets containing 5-25% B. The thymus contained mostly type II glucocorticoid receptors, which did not up-regulate 3 h or 5 days after ADX.
Acute sc injection of B (10–34 μg/g BW) in 10-day-old rats inhibited ADX-induced ACTH secretion within 30 min, and the estimated half-time for the inhibition was 40 min. By 2 h after B injection, plasma ACTH levels were comparable to those in sham-operated animals. Finally, a dose-dependent decrease in ADX-induced ACTH secretion was observed in 10-day-old rats replaced with various B pellet concentrations. Five to 25% B pellets effectively suppressed ACTH release 5 days after ADX and produced elevated circulating levels of B. In contrast, lower B concentrations (0.5–2% B) did not change ACTH or B concentrations significantly compared to those in ADX pups.
In conclusion, these results show that 1) an adult-like pattern and time course of the ACTH response to adrenalectomy are observed in 5- to 10-day-old neonates, suggesting that there was functional activation of central components that drove the pituitary; and 2) inhibition of ADX-induced ACTH secretion by B occurs relatively fast and with an IC50 of about 1 nM, compatible with association of this steroid with central high affinity glucocorticoid receptors. Therefore, our results strongly argue against a central insufficiency in corticotropin-releasing factor/ arginine vasopressin production during the neonatal period as a major cause of the stress hyporesponsive period. (Endocrinology127: 832–842, 1990)
