Modeling the Involvement of the HypothalamicPituitary-Adrenal and Hypothalamic-Pituitary-Gonadal Axes in Autoimmune and Stress-Related Rheumatic Syndromes in Women

Autoimmune and stress-related rheumatic diseases are significantly more common in women than in men. Our group has focused on the role of two principal neuroendocrine axes, the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis, in this increased susceptibility to rheumatic disease. We review the physiology of the HPA and HPG axes and discuss their reciprocal interactions. Mechanisms by which hormones of the HPA and HPG axes influence the immune system and modulate the course of autoimmune inflammatory diseases in animal models of rheumatic disease are described. In addition, we review the data suggesting the importance of these neurohormonal systems in rheumatic diseases. These data provide insights into why women may be at increased risk and how we might better understand the mechanisms that provoke expression of rheumatic diseases in women. To advance research in this area, it is critical to develop methods to evaluate the function of the neuroendocrine axes. Secretion of both HPA and HPG axis hormones, particularly the hormones of the hypothalamus and anterior pituitary, is largely by intermittent pulses. In addition, the HPA axis exhibits a profound circadian, or near 24-hour, variation, and HPG axis hormones fluctuate over the monthly cycle. These factors make meaningful analysis of these axes quite complex. We discuss models used in the analyses of neuroendocrine axes and the use of challenge testing to assess the integrity of neuroendocrine axes.