Systems neuroendocrinology in ME/CFS and long COVID: a chronobiological framework for hormone-based research

Jun 19, 2026Frontiers in neuroendocrinology

Hormone system changes over time in ME/CFS and long COVID

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Abstract

Neuroendocrine dysfunction is increasingly recognized in ME/CFS and Long COVID.

Changes in steroid, peptide, and neuropeptide hormone levels have been observed in both conditions.
The timing and integration of hormonal changes within broader physiological systems have not been thoroughly examined.
The hypothalamic-pituitary axes, which regulate various bodily functions, are affected in ME/CFS and Long COVID.
Sex hormone signaling is particularly vulnerable, which may relate to the higher prevalence of these conditions in females.
Accurate hormone measurement and time-structured sampling are necessary to identify significant biological differences.
A framework is proposed that incorporates chronobiology and multi-omic analyses to study endocrine mechanisms and symptom variability.

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Hormonal dysregulation is increasingly reported in ME/CFS and Long COVID, yet the broader role of neuroendocrine disruption in these conditions remains underexplored. While changes in steroid, peptide, and neuropeptide hormones have been identified, these findings are often considered in isolation and without attention to their timing or integration within broader physiological systems. The hypothalamic-pituitary axes regulate endocrine, immune, autonomic, nervous, and metabolic functions, systems commonly affected in both conditions, yet their circadian and menstrual dynamics are rarely investigated. In this review, we examine the evidence for neuroendocrine dysfunction in ME/CFS and Long COVID, focusing on hormone output, functional assays, receptor expression, and the coordination of endocrine biorhythms. Sex hormone signalling emerges as a key area of vulnerability, particularly given the female predominance in both conditions and the complexity of reproductive hormone regulation. We argue that accurate hormone measurement and time-structured sampling, including circadian and menstrual rhythms, are essential for detecting meaningful biological differences. By embedding chronobiology-aware, dense-sampling strategies and integrating multi-omic analyses into multi-system study designs, we outline a framework for investigating dynamic endocrine mechanisms underlying symptom variability and multisystem dysfunction, which may ultimately support the development of more targeted, personalised interventions.

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Systems neuroendocrinology in ME/CFS and long COVID: a chronobiological framework for hormone-based research

Abstract

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