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Preprint WatchModerateJune 20th, 2026

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.

Chronic oral contraceptive exposure disrupts region-specific glucocorticoid receptor and mineralocorticoid receptor signaling and impairs glucocorticoid negative feedback.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The indexed NR3C1 failure on file is exicorilant in metastatic castration-resistant prostate cancer, a glucocorticoid receptor program recorded as an efficacy failure with a glucocorticoid-receptor bypass mechanism (exicorilant-mcrpc-gr-bypass-fourth-failure). This preprint reports that glucocorticoid receptor signaling is regulated in a strongly region-specific and context-dependent way, with opposite directional effects across hippocampal subregions and the PVN. That context dependence aligns with the broader reason glucocorticoid receptor modulation is hard to translate, since the same receptor produces heterogeneous, tissue-specific outputs. The preprint studies a neuroendocrine setting rather than prostate cancer, so it supports the mechanistic theme behind the indexed efficacy failure without directly testing it.

Abstract excerpt

Combined oral contraceptives modulate the hypothalamic-pituitary-adrenal axis. In a mouse model of ethinyl estradiol plus levonorgestrel exposure, basal corticosterone was unchanged but glucocorticoid receptor (GR)-mediated negative feedback was impaired. Region-specific effects were found: enhanced GR-dependent signaling and prolonged Fkbp5 induction in dorsal hippocampus, enhanced mineralocorticoid receptor (MR)-dependent signaling in ventral hippocampus, and reduced MR expression in the PVN. The data show chronic exposure disrupts GR- and MR-dependent regulation across stress-related brain regions.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.