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bioRxiv · 10.64898/2026.06.15.731933

Region-specific regulation of glucocorticoid and mineralocorticoid receptor signaling in a mouse model of oral contraceptive exposure

Schuh, K. M.·Woock, M. G.·Vaandrager, M. J.·Romano, E. G.·He, Y.·Ludmir, D.·Tronson, N. C.
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Abstract

Combined oral contraceptives (OCs), containing synthetic estrogen and a progestin such as levonorgestrel (LVNG), are widely used, and up to 10% of users experience adverse mood states and increased depression risk. It is well-established that OCs modulate the hypothalamic-pituitary-adrenal (HPA) axis and blunt the cortisol responses to acute stress. This interaction with stress regulatory pathways is one mechanism by which OCs might impact mood. Here, we used a mouse model of OC exposure (ethinyl estradiol (EE) + LVNG) to investigate how OCs affect regulation of the diurnal CORT cycle and stress-related signaling in the dorsal and ventral hippocampus and paraventricular nucleus of the hypothalamus (PVN). We found that EE+LVNG did not alter basal corticosterone (CORT) levels, but impaired glucocorticoid receptor (GR) - mediated negative feedback in the dexamethasone suppression test. Molecular analyses revealed distinct, region-specific effects. In the dorsal hippocampus, EE+LVNG enhanced glucocorticoid receptor (GR)-dependent gene signaling and prolonged Fkbp5 induction. In the ventral hippocampus, EE+LVNG enhanced mineralocorticoid receptor (MR)-dependent signaling and reduced stress-induced corticotropin-releasing factor expression. In the PVN, EE+LVNG reduced MR expression and modulated MR-dependent signaling. Together, these findings demonstrate that chronic OC exposure disrupts GR- and MR-dependent regulation across stress-related brain regions and impairs glucocorticoid feedback, providing potential mechanisms by which OCs blunt stress responsivity, modify long-term HPA-axis function, and increase susceptibility or resilience to stress and depression.

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Schuh, K. M., Woock, M. G., Vaandrager, M. J., Romano, E. G., He, Y., Ludmir, D., Tronson, N. C.. 2026-06-19. Region-specific regulation of glucocorticoid and mineralocorticoid receptor signaling in a mouse model of oral contraceptive exposure. https://doi.org/10.64898/2026.06.15.731933

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