ADRENALECTOMY IN THE NEONATE - ADULT-LIKE ADRENOCORTICAL SYSTEM RESPONSES TO BOTH REMOVAL AND REPLACEMENT OF CORTICOSTERONE

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 IC50of 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 fig/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. © 1990 by The Endocrine Society.