Traumatic brain injury (TBI) is a major health problem affecting millions of people worldwide and leading to death or permanent damage. TBI affects the hypothalamic–pituitary–adrenal (HPA) axis either by primary injury to the hypothalamic–hypophyseal region or by secondary vascular damage, brain, and/or pituitary edema, vasospasm, and inflammation. Neuroendocrine dysfunctions after TBI have been clinically described in all hypothalamic–pituitary axes. We established a mild TBI (mTBI) in rats by using the controlled cortical impact (CCI) model. The hypothalamus, pituitary, and adrenals were collected in the acute (24 h) and chronic (30 days) groups after TBI, and we investigated transcripts and protein-related autophagy (Lc3, Bcln1, P150, Ulk, and Atg5) and apoptosis (pro-caspase-3, cleaved caspase-3). Transcripts related to autophagy were reduced in the hypothalamus, pituitary, and adrenals after TBI, however, this was not reflected in autophagy-related protein levels. In contrast, protein markers related to apoptosis increased in the adrenals during the acute phase and in the pituitary during the chronic phase. TBI stresses induce a variation of autophagy-related transcripts without modifying the levels of their proteins in the HPA axis. In contrast, protein markers related to apoptosis are increased in the acute phase in the adrenals, which could lead to impaired communication via the hypothalamus, pituitary, and adrenals. This may then explain the permanent pituitary damage with increased apoptosis and inflammation in the chronic phase. These results contribute to the elucidation of the mechanisms underlying endocrine dysfunctions such as pituitary and adrenal insufficiency that occur after TBI. Although the adrenals are not directly affected by TBI, we suggest that the role of the adrenals along with the hypothalamus and pituitary should not be ignored in the acute phase after TBI.

Traumatic brain injury (TBI) induces complex molecular and neuroendocrine alterations that extend beyond the site of injury. The hypothalamic–pituitary–adrenal (HPA) axis, a hierarchically organized neuroendocrine system composed of the hypothalamus, pituitary gland, and adrenal glands, plays a central role in coordinating stress and metabolic homeostasis. Despite its critical importance, the temporal transcriptional mechanisms underlying HPA axis dysregulation following TBI remain poorly understood, particularly in relation to coordinated neuronal injury and regeneration processes. This study aimed to investigate the time-dependent transcriptional dynamics of genes associated with neuronal injury and regeneration within the HPA axis following experimental TBI. Moderate-to-severe TBI was induced in Sprague–Dawley rats using a controlled cortical impact (CCI) model. Animals were allocated into sham, acute (24 h), and chronic (30 days) groups. Transcript profiles of 24 HPA axis- and neuroregeneration-related genes were analyzed in hypothalamic, pituitary, and adrenal tissues using quantitative real-time PCR, with normalization to a housekeeping gene and statistical evaluation of differential expression across time points. TBI induced distinct, tissue-specific, and time-dependent transcriptional alterations across the HPA axis. In the acute phase, stress-response genes showed divergent regulation between central and peripheral tissues, whereas the chronic phase was characterized by transcriptional reorganization involving neurotrophic, metabolic, and neuroendocrine pathways. Key regulators such as Hif1a, Rad18, Avp, Gata3, and OxtR exhibited significant and region-specific expression changes. These findings demonstrate that TBI triggers coordinated yet heterogeneous transcriptional responses within the HPA axis, linking central injury to systemic endocrine adaptation. This study provides novel insight into the molecular basis of neuroendocrine dysfunction and recovery after TBI and identifies candidate targets for future therapeutic strategies.