Objective: A key component in the body’s stress response, the hypothalamic-pituitary-adrenal (HPA) axis, orchestrates changes several biological systems, although few models of its function account for these interactions. HPA dysfunction has been associated with numerous chronic diseases including Gulf War illness (GWI) and chronic fatigue syndrome (CFS). Here we model HPA function and it’s interaction with sex hormone regulation and immune response to explore the role of gender in homeostatic regulation and the perpetuation of chronic illness

Methods:We use documented data of molecular/cellular signaling from biochemical/physiological literature to construct a diagram of interactions between the HPA, immune system and sex hormone axis. Logic rules are applied to this connectivity diagram to predict the stable homeostatic behaviors of the total system. Clinical endocrine/immune profiles of male GWI and female CFS subjects, obtained from an ongoing study, are compared against controls using standard t-test statistics. Using a meta-analysis of these statistical significances the probabilities of alignment of GWI and CFS with model predicted states are calculated.

Results: Male GWI subjects showed the greatest alignment with a predicted state of hypercortisolism, low testosterone and a shift towards a Th1 immune response. Female CFS subjects aligned most significantly with a predicted hypocortisolic, high estradiol, and a shift towards an anti-inflammatory Th2 activation state.

Conclusion: Results support a role for homeostatic drive in perpetuating dysfunctional cortisol levels through interaction with the immune system and sex hormone axis. Additionally, results suggest that this drive can perpetuate sexually dimorphic responses in GWI and CFS due to the inherent differences in the male and female sex systems.