Review
Estrogen, prolactin, and autoimmunity: actions and interactions

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Abstract

Estrogen and prolactin have a reciprocal endocrinologic relationship and both hormones have pleiotropic effects on the immune system. Despite the presence of a number of confounding variables, these hormones modulate autoimmunity; however, mechanisms by which this modulation occurs remain obscure. Estrogen appears to suppress cell-mediated and augment humoral-based immunity. Prolactin appears to stimulate both cell and humoral-based immunity. Both hormones have been shown to modulate IFNγ secretion. Similar evidence in experimental models, human autoimmune disease, and during pregnancy in autoimmune disease patients suggests disparate effects of estrogen and prolactin on autoimmune responses and disease pathogenesis. In the NZB×NZW F1 mouse model of lupus, prolactin accelerates disease expression, whereas estrogen, devoid of its prolactin stimulating properties, is immunosuppressive and inhibits IL-2 production. Estrogen, because of its endocrinologic and immune effects, may directly or indirectly stimulate or inhibit immune responses. These dichotomous effects have limited its successful pharmacologic manipulation in human autoimmune disease with estrogen compounds, tamoxifen, oral contraceptives, antigonadotropic agents, or ovulation induction regimens. In contrast, reduction of immunostimulatory concentrations of prolactin with bromocriptine has successfully suppressed development or expression of murine and human autoimmune disease. Further investigation into actions and interactions of estrogen and prolactin with autoimmunity will provide a better understanding of the female preponderance of autoimmunity and facilitate a more rational approach to hormonal immunotherapy.

Section snippets

Estrogen and prolactin: actions and interactions

Estrogens are aromatized steroid hormones synthesized from a cholesterol backbone and produced predominantly in the ovary, although some aromatization may occur in adipose tissue. Estrogens may occur in many forms; 17-β-estradiol is the most common circulating form [1]. Differences in estrogenic potencies and actions of their metabolites exist and may be important in the modulation of immunity or autoimmunity [60], but are beyond the focus of this review. Precursors to estrogen in the steroid

Immunologic effects of estrogen and prolactin

Estrogen and prolactin have multiple effects on lymphohematopoietic cells that are summarized in Table 1 and reviewed in depth by others [11], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47]. In brief, estrogen has been shown to modulate lymphoid cell growth and differentiation, proliferation, antigen presentation, cytokine production, antibody production,

Estrogen, prolactin and autoimmunity in the B/W mouse model of SLE

In the 1970s, investigation into hormonal modulation of autoimmunity burgeoned through utilization of the B/W mouse model of SLE. The B/W mouse model of autoimmunity manifests disease similar to human SLE in its development of autoantibodies, immune complex glomerulonephritis, and earlier disease development in the female B/W mouse [78], [79]. Female B/W mice have higher production of IFNγ compared to their male counterparts [80], with IFNγ being crucial to the development of autoimmune disease

Estrogen, prolactin, and human SLE

Several lines of evidence have suggested that estrogen or its metabolites contribute to the female predilection or to exacerbations of SLE, based primarily on clinical observations of cyclic SLE flares, exacerbations by oral contraceptive administration, and abnormal steroid metabolism [94]. Alternatively, some observations have suggested that estrogen ameliorates human autoimmune disease [95], [96], [97], [98], [99], [100]. In SLE, administration of the estrogen receptor blocker, tamoxifen,

Estrogen, prolactin and autoimmunity and pregnancy

Following conception, pregnancy in mammals is characterized by progressive rises in serum estrogen, progesterone and prolactin concentrations as well as a number of placental hormones (which are beyond the focus of discussion in this review). Following delivery, estrogen and progesterone secretion drops while prolactin secretion remains high, particularly in nursing mammals [1]. Multiple changes in the immune system occur during pregnancy, which have been globally characterized as suppression

Significance and potential immunopharmacology

Identification of sex-based immunoregulatory differences and mechanisms of hormonal immunomodulation would be of potential benefit to both women and men as it would provide a better understanding of immunity and probable autoimmune disease pathogenesis as well as a basis for incisive in vivo investigations of disease processes. Understanding differences should ultimately lead to the more logical and effective use of hormones, hormone antagonists, and immunotherapy as interventions in

Conclusion

Extensive evidence of pleiotropic immunomodulatory effects and pertinent clinical observations firmly establishes roles for both estrogen and prolactin. Their complex actions and interactions, illustrated in Fig. 1, preclude dogmatic conclusions regarding their immunomodulatory actions. Distinct hormonal modulation of the TH1/TH2 cytokine balance likely deviates immune and autoimmune responses in women throughout their lives and during pregnancy [138]. Although confounding factors will likely

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