The hypothalamic-pituitary-adrenal (HPA) and the hypothalamic-pituitary-gonadal (HPG) axis involvement, and/or response to the immune system activation, is now recognised in the development and maintenance of inflammatory and autoimmune conditions such as rheumatoid arthritis (RA).1

In female patients the immune response seems to depend more on the HPA axis, whereas in male patients it seems to depend more on the HPG axis. In particular, hypoandrogenism may have a pathogenetic role in male patients with RA, and in other autoimmune conditions (for example, systemic lupus erythematosus (SLE)), as androgens are considered natural immunosuppressors.2

Conversely, physiological concentrations of oestrogens seem to exert some immunoenhancing activities, at least on the humoral response. In addition, a range of physical/psychosocial stressors are also implicated in the activation of the HPA axis and the related altered HPG function in RA.3 ,4

Finally, the raised levels of neurotransmitters detected in RA synovial fluids, suggest that the peripheral nervous system also might contribute to the generation of the synovial inflammation (that is, neurogenic inflammation).5-8

A major unknown in the pathogenesis of RA is why immune mediated inflammation begins and develops within joints. A central role in understanding RA pathogenesis lies in the comprehension of arthrotropism of antigens and inflammatory cells for joints and in learning what specific receptors, mediators, and chemotactic gradients are active in focusing the immune mediated inflammation within the synovial tissue.

Undoubtedly, the synovial tissue in RA can be regarded as the “target tissue”, in which the sexual dimorphism in immune response to relevant trigger antigens is present and involves mainly synovial macrophages as well as fibroblasts and lymphocytes.9-15

Therefore, an intricate balance with bidirectional interactions between soluble mediators, released by the neuroendocrine system (that is, neurotransmitters and steroid hormones) and products of activated cells of the immune/inflammatory system (that …