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This review synthesizes current evidence on neuroendocrine mechanisms linking perceived and objective social disconnection to health consequences, emphasizing hypothalamic\u2013pituitary\u2013adrenal axis dysfunction, altered glucocorticoid signaling, and inflammatory pathways. Loneliness activates conserved transcriptional responses with upregulated proinflammatory gene expression and downregulated antiviral responses, mediated through sustained cortisol elevation and glucocorticoid resistance. Neural circuit alterations in reward processing, particularly the ventral tegmental area-nucleus accumbens pathway, contribute to anhedonia, social withdrawal, and cognitive decline. Sex differences in neuroendocrine responses reveal distinct hormonal profiles and circuit-specific adaptations. Emerging interventions targeting oxytocin and arginine vasopressin systems, alongside behavioral approaches addressing loneliness-induced cognitive biases, show promise. Critical research gaps include a mechanistic understanding of epigenetic modifications, sex-specific therapeutic responses, and translational applications across diverse populations. Understanding the endocrine\u2013behavior interface in social disconnection offers opportunities for targeted interventions addressing this growing public health challenge.<\/jats:p>","DOI":"10.3390\/ijms27010084","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T16:41:19Z","timestamp":1766594479000},"page":"84","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Hormonal and Behavioral Consequences of Social Isolation and Loneliness: Neuroendocrine Mechanisms and Clinical Implications"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1159-4573","authenticated-orcid":false,"given":"Volodymyr","family":"Mavrych","sequence":"first","affiliation":[{"name":"College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghaith K.","family":"Mansour","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0024-3751","authenticated-orcid":false,"given":"Ahmad W.","family":"Hajjar","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9496-9754","authenticated-orcid":false,"given":"Olena","family":"Bolgova","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Vitale, E.M., and Smith, A.S. 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