Stress or glucocorticoid (GC) treatment in perinatal life can induce long-term changes in the sensitivity of the HPA axis to the feedback actions of GCs and, hence, in GC secretion. These changes have been ascribed largely to changes in the sensitivity of the limbic system, and possibly the hypothalamus, to GCs. Surprisingly, the possibility that early life stress/GC treatment may also exert irreversible effects at the pituitary level has scarcely been addressed. Accordingly, we have examined the effects of pre- and neo-natal dexamethasone treatment on the adult male pituitary gland, focusing on (a) the integrity of the acute annexin 1 (ANXA1) -dependent inhibitory actions of GCs on ACTH secretion, a process requiring ANXA1 release from folliculo-stellate (FS) cells and (b) the morphology of FS cells and corticotrophs. Dexamethasone was given to pregnant (days 16-19) or lactating (days 1-7 post-partum) rats via the drinking water (1 µg/ml); controls received normal drinking water. Pituitary tissue from the offspring was examined ex vivo at day 90. Both treatment regimes reduced ANXA1 expression, as assessed by western blotting and quantitative immunogold labeling. In particular, the amount of ANXA1 located on the outer surface of the FS cells was reduced. By contrast, interleukin-6 (IL-6) expression was increased, particularly by the prenatal treatment. Pituitary tissue from untreated control rats responded to dexamethasone with an increase in cell surface ANXA1 and a reduction in forskolin-induced ACTH release. In contrast, pituitary tissue from rats treated prenatally or neonatally with dexamethasone was unresponsive to the steroid although, like control tissue, it responded readily to ANXA1 which readily inhibited forskolin-driven ACTH release. Prenatal dexamethasone treatment reduced the size but not the number of FS cells. It also caused a marked reduction in corticotroph number and impaired granule margination without affecting other aspects of corticotroph morphology. Similar but less marked effects on pituitary cell morphology and number were evident in tissue from neonatally treated rats. Our study shows that, when administered by a non-invasive process, perinatal GC treatment exerts profound effects on the adult pituitary gland, impairing the ANXA1-dependent GC regulation of ACTH release and altering the cell profile and morphology.