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28 Co-occurring conditions like anxiety, depression, stress, and sleep disorders can be contributors, while disturbances that are difficult to diagnose, such as dysregulated stress reactivity, neurotransmitter imbalance, inflammation, mitochondrial dysfunction, free radical damage, hormonal imbalance, and metabolic disturbance, as well as crosstalk between these factors, may also play a role

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On the other hand, the concept of non-genomic or cytoplasmic response was introduced in 1967, when Szego and Davis observed an increase in cyclic adenosine monophosphate (cAMP) in the MCF-7 breast cancer cell line pretreated with estrogens (Szego and Davis, 1967)