Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner

TLDR

The adrenal gland, a key component of the HPA axis, increases in weight with chronic stress, yet it is unclear whether this growth reflects hyperplasia or hypertrophy, its subregional distribution, or changes in ACTH sensitivity versus maximal glucocorticoid output. The study investigates how a 14‑day chronic variable stress paradigm affects adrenal growth and corticosterone production in adult male rats. Using stereological cell counting with Ki67 and nuclear markers across adrenal zones, the authors mapped stress‑induced hyperplasia in the outer zona fasciculata, hypertrophy in the inner zona fasciculata and medulla, and reduced cell size in the zona glomerulosa. Chronic variable stress elevates maximal ACTH‑stimulated corticosterone release, increases adrenal weight, DNA/RNA content, and RNA/DNA ratio, and induces subregion‑specific hyperplasia and hypertrophy, suggesting that stress‑driven adrenal growth enhances maximal glucocorticoid output.

Abstract

The adrenal gland is an essential stress-responsive organ that is part of both the hypothalamic-pituitary-adrenal axis and the sympatho-adrenomedullary system. Chronic stress exposure commonly increases adrenal weight, but it is not known to what extent this growth is due to cellular hyperplasia or hypertrophy and whether it is subregion specific. Moreover, it is not clear whether increased production of adrenal glucocorticoid after chronic stress is due to increased sensitivity to adrenocorticotropic hormone (ACTH) vs. increased maximal output. The present studies use a 14-day chronic variable stress (CVS) paradigm in adult male rats to assess the effects of chronic stress on adrenal growth and corticosterone steroidogenesis. Exogenous ACTH administration (0-895 ng/100 g body wt) to dexamethasone-blocked rats demonstrated that CVS increased maximal plasma and adrenal corticosterone responses to ACTH without affecting sensitivity. This enhanced function was associated with increased adrenal weight, DNA and RNA content, and RNA/DNA ratio after CVS, suggesting that both cellular hyperplasia and hypertrophy occurred. Unbiased stereological counting of cells labeled for Ki67 (cell division marker) or 4,6-diamidino-2-phenylindole (nuclear marker), combined with zone specific markers, showed that CVS induced hyperplasia in the outer zona fasciculata, hypertrophy in the inner zona fasciculata and medulla, and reduced cell size in the zona glomerulosa. Collectively, these results demonstrate that increased adrenal weight after CVS is due to hyperplasia and hypertrophy that occur in specific adrenal subregions and is associated with increased maximal corticosterone responses to ACTH. These chronic stress-induced changes in adrenal growth and function may have implications for patients with stress-related disorders.