Aging and aging related illnesses such as cancer have been associated with 
inflammatory changes. Cancer-related behavioral comorbidities such as fatigue, 
sleep disturbances, depression have also been associated with inflammation, 
hypothalamic-pituitary-adrenal (HPA) axis dysregulation and other neuroendocrine 
changes. From a clinical perspective, cancer-related fatigue demonstrates 
striking similarities with the cytokine-induced sickness phenomenon in animal 
models. Thyrotopin-releasing hormone (TRH) plays a homeostatic role in its 
interaction with several biological systems, including a critical role in its 
interactions with the immune system. Considerable evidence supports a pivotal 
role for TRH in the inflammatory processes with specific relevance to the 
"cytokine-induced sickness behavior" paradigm. Additionally, TRH exerts arousing 
and analeptic effects in instances of behavioral depression. In a small 
proof-of-concept study conducted by our group, we investigated TRH 
administration as a treatment fatigue in cancer survivors in comparison with 
saline administration using a double-blind, crossover design. We also evaluated 
impact of TRH/saline administration on the inflammatory markers in these 
patients. TRH administration was associated with significant improvement (p < 
0.05) in fatigue levels as measured by the Visual Analog Scale-Energy (VAS-E), 
was associated with significant (p < 0.05) improvement in sleep disturbances and 
improved quality of life. Notably, TRH administration was associated with 
decrease in C-reactive protein (CRP) levels, a marker of inflammation. This 
decrease in CRP level with TRH administration was associated with improvement in 
energy levels as measured by the VAS-E. The present review supports potential 
utility of TRH-based therapeutics in medical and psychiatric disorders with 
underlying inflammatory processes.