Women are more prone to autoimmune diseases, hormone-dependent cancers, osteoporosis, and neurodegenerative diseases with advancing age. The age-associated increase in the incidence and development of diseases and cancer is the result of a decline in immunocompetence facilitated by dysfunctions of nervous system and endocrine system. Reciprocal interactions between the brain and primary (bone marrow and thymus) and secondary (spleen and lymph nodes) lymphoid organs, via neurotransmitters and immune molecules determine an individualu2019s health or disease status. One of the major contributing factors for this imbalance in homeostatic functioning of the neuroendocrine- immune system is estradiol (E2) that exerts its effects through alterations in the production of neurochemicals and immune mediators. Estrogenu2019s reported beneficial effects such as anti-inflammatory and neuroprotective functions and deleterious effects of cancer progression are dependent upon age of women, type of cells and receptors, and the intracellular pathways and signaling molecules involved in mediating its effects. It is imperative that the diverse effects of estrogen on organ systems should be investigated via a longitudinal study beginning with early middle-aged rats to understand the long-term of exposure of estrogen on health and development of diseases. In this review, we present evidence for the biphasic effects of E2 on neural-immune interactions in the thymus, spleen, and lymph nodes and brain areas of early middle-aged female rats. These effects were dependent on pro/antioxidant status, and expression of growth factors and intracellular signaling molecules that are crucial to the neuronal plasticity influencing neuroprotection and inflammatory processes causing neurodegeneration.

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