Attenuation of hypothalamic-pituitary-adrenal axis stress responses in late pregnancy: Changes in feedforward and feedback mechanisms

The hypothalamic-pituitary-adrenal axis is hyporesponsive to stress in late pregnancy, exemplified as reduced adrenocorticotropic hormone (ACTH) and c orticosterone responses to restraint, but the mechanisms are unknown. We in vestigated forward drive and negative feedback upon the hypothalamic-pituit ary-adrenal axis in pregnant rats. Corticotropin-releasing hormone (CRH) an d vasopressin mRNA expression in the parvocellular paraventricular nucleus and mineralocorticoid and glucocorticoid receptor expression in the paraven tricular nucleus and hippocampus were quantified with in situ hybridization . Because it can enhance the corticosterone negative feedback signal, 11 be ta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) bioactivity in these brain regions and anterior pituitary was measured in vitro, and ACTH and co rticosterone stress responses were measured after intracerebroventricular g lycyrrhetinic acid, an 11 beta-HSD inhibitor. Changes in corticosterone fee dback on ACTH secretion were examined after pharmacological adrenalectomy b y metyrapone and aminoglutethimide. Parvocellular paraventricular nucleus C RH mRNA content was reduced on day 21 and the CRH mRNA : vasopressin mRNA r atio was unaltered, indicating decreased production of both CRH and vasopre ssin. An increase in glucocorticoid receptor mRNA expression in the dentate gyrus (mineralocorticoid receptor mRNA expression was unaltered) and incre ased 11 beta-HSD1 activity in the paraventricular nucleus and anterior pitu itary suggest an increase in slow negative feedback mechanisms in pregnancy , but glycyrrhetinic acid did not modify the stress response. After metyrap one/aminoglutethimide treatment, corticosterone decreased ACTH secretion mo re slowly in pregnancy, indicating a decrease in rapid feedback sensitivity . Thus, reduced forward drive rather than increased effectiveness of glucoc orticoid negative feedback may underlie stress hyporesponsiveness of the hy pothalamic-pituitary-adrenal axis in pregnancy.