Endocrine Noise: Sex-Specific Disruption of Hypothalamic–Pituitary–Adrenal (HPA) Axis by Endocrine-Disrupting Chemicals

Environmental chemicals are rarely considered stressors in the way that psychological or physical stressors are. Yet many endocrine-disrupting chemicals (EDCs) interact with the body’s core stress response system. This review examines how EDCs alter hypothalamic–pituitary–adrenal (HPA) regulation and how biological sex influences those responses. Drawing on human epidemiological data and experimental models, we describe how EDC exposure affects cortisol dynamics, feedback sensitivity, and adrenal signaling, with a particular focus on sex-dependent outcomes. We propose the concept of endocrine noise to describe how low-dose, often mixed EDC exposures introduce persistent interference into hormone signaling without necessarily causing overt endocrine deficiency or excess. In this framework, EDCs act as chronic, low-grade stressors that reset the timing, feedback precision, and rhythmic organization of the HPA axis rather than as isolated reproductive toxicants. We argue that EDCs should be understood as chronic, context-dependent stress modifiers that reshape sex-specific “risk architectures” for affective, metabolic, and immune disorders. Recognizing sex-specific HPA architecture and endocrine noise has immediate implications for study design and regulation, including the need for sex-stratified analyses, circadian-sensitive sampling of cortisol, and risk assessments that consider how the same exposure can push female and male stress systems in divergent directions.