Figure 5.A proposed model of the role of different hormones in regulation of innate, and Th1 and Th2 cytokine profiles during pregnancy. Hypothalamic CRH stimulates the secretion of pituitary ACTH, which in turn triggers the secretion of cortisol from the adrenal cortex. During human pregnancy, the placenta is the major source of circulating CRH. The placenta also secretes IL-10 that may stimulate humoral and suppress cellular immunity. The sympathetic system innervates all peripheral tissues, including blood vessels and lymphoid organs. Upon activation, the sympathetic nerve terminals in these organs release NE locally and into the blood stream. Cortisol, NE, 1,25(OH)2 vitamin D3, estradiol and progesterone have multiple and divergent effects upon the immune system. *Cortisol does not affect but NE up-regulate the production of IL-10 by monocytes. Note that cortisol and estradiol up-regulate IL-10, while progesterone potentiate IL-4 production by Th2 lymphocytes. In addition, estradiol stimulates the activity of the CRH neurons, and increases local NE concentrations by blocking its uptake. Thus,in vivo,estradiol might amplify the effects of cortisol and NE. The net result of these complex hormonal effects is suppression of IL-12 and TNF production by monocytes, whereas peripheral lymphocytes secrete less IFN- and IL-2 but more IL-4 and IL-10, particularly in the 3rd trimester. This hormonally induced Th2 shift may suppress Th1-related diseases such as RA and MS during pregnancy, while the rebound of IL-12 and TNF production, and Th1 responses in the postpartum may facilitate the flares or the onset of these diseases. Note that several other factors, besides hormones (e.g. antibodies, soluble cytokine receptors, etc.) that most likely are also involved in the modulation of Th1/Th2 balance during pregnancy and postpartum, are not discussed here.Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; IL, interleukin; LC, locus ceruleus; Mo, monocyte; NE, norepinephrine; PVN, paraventricular nucleus; Th, T helper cell; TNF, tumor necrosis factor. (From reference 54).