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The HPG axis regulates reproductive and gonadal hormone activities and significantly impacts the body\u2019s response to acute and chronic illnesses. This review explores the fundamental functions of the HPG axis, modifications under critical conditions, and impacts on disease progression and treatment outcomes. In addition, it examines interactions between sex hormones and biomolecules like cytokines and gastrointestinal microorganisms, highlighting their roles in immune response regulation. Clinically, this knowledge can enhance patient prognoses. 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