"There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox.
This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17β-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor α and β depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens.
This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems."
"Estrogens influence systemic response systems by reducing the cytokine-stimulated ACTH and cortisol release, by increasing substance P signaling and sensitization to painful stimuli (increase of neurogenic inflammation), and by increasing signaling through proinflammatory α-adrenergic pathways (Fig. 4). These estrogen effects can partly explain the sexual dimorphism in chronic inflammatory diseases."
"In conclusion, immune stimuli (foreign antigens or autoantigens) and respective immune responses, the cell types involved (not only immune cells), the target organ, the reproductive status in a woman and timing of E2 administration in relation to the disease process, concentration of estrogens (dual effects), expression of ERα and ERβ (and their isoforms) depending on the microenvironment and the cell type, and intracellular metabolism of estrogens all play important roles in inflammatory diseases. In addition, systemic supersystems such as the HPA axis, the sensory nervous system, and the SNS can be influenced by estrogens to establish a proinflammatory milieu.
This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned influencing factors. This review also explains that a uniform concept for the action of estrogens cannot be found for all known chronic inflammatory diseases (Figs. 3 and 5). Nevertheless, for strictly B cell-dependent diseases such as those shown in Fig. 5, the female to male preponderance can be explained by the propagating effects of estrogens (but possibly also of progesterone). The smaller the influence of B cells and the bigger the weight of T cells and other cells, the less evident is the sex dimorphism in chronic inflammatory diseases (Fig. 5). In addition, because men never experience high estrogen (or progesterone) levels like women during pregnancy, the apparent gender dimorphism of chronic inflammatory diseases during the reproductive period of women can be explained. In addition, and this was not reported here, higher androgen levels in men most often exert inhibitory effects on many immune phenomena, which is an other important argument for why women with low androgen levels are protected from infectious diseases but more prone to B cell-dependent autoimmunity. Finally, we should not forget that sexual dimorphism of diseases may also depend on factors independent of sex hormones (588)."
Fig. 3. Relation between estrogen levels and inflammatory diseases. Red indicates that estrogens at respective concentrations exert proinflammatory effects, whereas green demonstrates estrogen levels with an antiinflammatory effect. In this summary, RA and MS (upper block) are divided according to the underlying dominant cell type involved. Today, we know that in a fraction of patients B cells play a dominant role, whereas in another group of patients macrophages, dendritic cells, T cells, and other non-B cells are predominant (164 165 166 167 ). In diseases with a B cell predominance, estrogens at all levels stimulate the proinflammatory process, whereas in disease without a strong B cell involvement, estrogens demonstrate a dual role: at low concentrations estrogens stimulate, and at high levels, estrogens inhibit the disease process. A somewhat different picture appears for prostatitis and LPS-induced Kupffer cell-dependent shock where estrogens seem to sensitize the inflammatory response. DC, Dendritic cell; NK cell, natural killer cell.
