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Abstract

The immunomodulatory effects of sex hormones are a major factor leading to sexual dimorphism of the human immune system and to the higher susceptibility of females to autoimmune diseases. Data regarding the immunomodulatory effect of estrogens are abundant, but far less is known about progestogens. Recent data indicate that female sex hormones influence immunity and autoimmunity in very different ways: estrogens generally enhance the immune response and increase susceptibility to autoimmunity, while progestogens protect against autoimmunity.

Progesterone immunomodulation during pregnancy is of special interest. One of the challenges of pregnancy is to keep the mother safe from infections while keeping the fetus safe from the maternal immune system. Progesterone's immunomodulatory effects may be crucial in balancing these opposing needs. Progesterone enhances Th2 and Treg activity and decreases Th1 and Th17 activity. These actions may underlie the remission of Th1- and Th17- mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis during the high progesterone state of pregnancy. Consequently, progestogens have been reported to be potential treatment for these diseases.

Another aspect of the interaction of progestogens with the immune system is progestogen hypersensitivity. This condition is characterized by a hypersensitive reaction to endogenous or exogenous progestogens. The diagnosis is challenging and while effective treatment can sometimes be achieved through suppression of ovulation or progestogen desensitization, in some cases immunosuppressive drugs or even oophorectomy may be required.

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References

  1. Fairweather DS, Frisancho-Kiss S, Rose NR. Sex differences in autoimmune disease from a pathological perspective. Am J Pathol. 2008;173:600–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. McCombe PA, Greer JM, Mackay IR. Sexual dimorphism in autoimmune disease. Curr Mol Med. 2009;9:1058–79.

    Article  CAS  PubMed  Google Scholar 

  3. Quintero OL, Amador-Patarroyo MJ, Montoya-Ortiz G, Rojas-Villarraga A, Anaya JM. Autoimmune disease and gender: plausible mechanisms for the female predominance of autoimmunity. J Autoimmun. 2012;38:J109–19.

    Article  CAS  PubMed  Google Scholar 

  4. Bouman A, Heineman MJ, Faas MM. Sex hormones and the immune response in humans. Hum Reprod Update. 2005;11:411–23.

    Article  CAS  PubMed  Google Scholar 

  5. Chen W, Mempel M, Schober W, Behrendt H, Ring J. Gender difference, sex hormones, and immediate type hypersensitivity reactions. Allergy. 2008;63:1418–27.

    Article  CAS  PubMed  Google Scholar 

  6. Scofield RH. Genetics of systemic lupus erythematosus and Sjögren’s syndrome. Curr Opin Rheumatol. 2009;21:448–53.

    Article  CAS  PubMed  Google Scholar 

  7. Bellott DW, Hughes JF, Skaletsky H, Brown LG, Pyntikova T, Cho TJ, et al. Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators. Nature. 2014;508:494–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Adams KM, Nelson JL. Microchimerism: an investigative frontier in autoimmunity and transplantation. JAMA. 2004;291:1127–31.

    Article  CAS  PubMed  Google Scholar 

  9. Hughes GC. Progesterone and autoimmune disease. Autoimmun Rev. 2012;11:A502–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Gargano J, Holzman C, Senagore P, Thorsen P, Skogstrand K, Hougaard D, Rahbar M, Chung H. Mid-pregnancy circulating cytokine levels, histologic chorioamnionitis and spontaneous preterm birth. J Reprod Immunol. 2008;79:100–10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Moura E, Mattar R, deSouza E, Torloni M, Goncalves-Primo A, Daher S. Inflammatory cytokine gene polymorphisms and spontaneous preterm birth. J Reprod Immunol. 2009;80:41–8.

    Article  Google Scholar 

  12. Miossec P, Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov. 2012;11:763–76.

    Article  CAS  PubMed  Google Scholar 

  13. Lee SK, Kim JY, Lee M, Gilman-Sachs A, Kwak-Kim J. Th17 and regulatory T cells in women with recurrent pregnancy loss. Am J Reprod Immunol. 2012;67:311–8.

    Article  CAS  PubMed  Google Scholar 

  14. Arck PC, Hecher K. Fetomaternal immune cross-talk and its consequences for maternal and offspring’s health. Nat Med. 2013;19:548–56.

    Article  CAS  PubMed  Google Scholar 

  15. Kaushic C, Roth K, Anipindi V, Xiu F. Increased prevalence of sexually transmitted viral infections in women: the role of female sex hormones in regulating susceptibility and immune responses. J Reprod Immunol. 2011;88:205–9.

    Article  Google Scholar 

  16. Kourtis AP, Read JS, Jamieson DJ. Pregnancy and infection. N Engl J Med. 2014;370:2211–8.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Rowe JH, Ertelt JM, Aguilera MN, Farrar MA, Way SS. Foxp3(+) regulatory T cell expansion required for sustaining pregnancy compromises host defense against prenatal bacterial pathogens. Cell Host Microbe. 2011;10:54–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Sakiani S, Olsen NJ, Kovacs WJ. Gonadal steroids and humoral immunity. Nat Rev Endocrinol. 2013;9:56–62.

    Article  CAS  PubMed  Google Scholar 

  19. Arnold JN, Wormald MR, Sim RB, Rudd PM, Dwek RA. The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu Rev Immunol. 2007;25:21–50.

    Article  CAS  PubMed  Google Scholar 

  20. Prados MB, La Blunda J, Szekeres-Bartho J, Caramelo J, Miranda S. Progesterone induces a switch in oligosaccharyltransferase isoform expression: consequences on IgG N-glycosylation. Immunol Lett. 2011;137:28–37.

    Article  CAS  PubMed  Google Scholar 

  21. Hughes GC, Clark EA. Regulation of dendritic cells by female sex steroids: relevance to immunity and autoimmunity. Autoimmunity. 2007;40:470–81.

    Article  CAS  PubMed  Google Scholar 

  22. Østensen M, Villiger PM. The remission of rheumatoid arthritis during pregnancy. Semin Immunopathol. 2007;29:185–91.

    Article  PubMed  Google Scholar 

  23. Hoffman GE, Merchenthaler I, Zup SL. Neuroprotection by ovarian hormones in animal models of neurological disease. Endocrine. 2006;29:217–31.

    Article  CAS  PubMed  Google Scholar 

  24. Hel Z, Stringer E, Mestecky J. Sex steroid hormones, hormonal contraception, and the immunobiology of human immunodeficiency virus-1 infection. Endocr Rev. 2010;31:79–97.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Munoz-Suano A, Hamilton AB, Betz AG. Gimme shelter: the immune system during pregnancy. Immunol Rev. 2011;241:20–38.

    Article  CAS  PubMed  Google Scholar 

  26. de Man YA, Dolhain RJ, van de Geijn FE, Willemsen SP, Hazes JM. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum. 2008;59:1241–8.

    Article  PubMed  Google Scholar 

  27. Østensen M, Villiger PM, Förger F. Interaction of pregnancy and autoimmune rheumatic disease. Autoimmun Rev. 2012;11:A437–46.

    Article  PubMed  Google Scholar 

  28. Latman NS. Relation of menstrual cycle phase to symptoms of rheumatoid arthritis. Am J Med. 1983;74:957–60.

    Article  CAS  PubMed  Google Scholar 

  29. de Man YA, Bakker-Jonges LE, Goorbergh CM, Tillemans SP, Hooijkaas H, Hazes JM, Dolhain RJ. Women with rheumatoid arthritis negative for anti-cyclic citrullinated peptide and rheumatoid factor are more likely to improve during pregnancy, whereas in autoantibody-positive women autoantibody levels are not influenced by pregnancy. Ann Rheum Dis. 2010;69:420–3.

    Article  PubMed  Google Scholar 

  30. Houtchens M. Multiple sclerosis and pregnancy. Clin Obstet Gynecol. 2013;56:342–9.

    Article  PubMed  Google Scholar 

  31. Vukusic S, Ionescu I, El-Etr M, Schumacher M, Baulieu EE, Cornu C, Confavreux C. The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART'MUS) trial: rationale, objectives and state of advancement. J Neurol Sci. 2009;286:114–8.

    Article  CAS  PubMed  Google Scholar 

  32. Andreoli L, Fredi M, Nalli C, Reggia R, Lojacono A, Motta M, Tincani A. Pregnancy implications for systemic lupus erythematosus and the antiphospholipid syndrome. J Autoimmun. 2012;38:J197–208.

    Article  CAS  PubMed  Google Scholar 

  33. Chabbert-Buffet N, Amoura Z, Scarabin PY, Frances C, Lévy DP, Galicier L, Wechsler B, Blétry O, Piette JC, Gompel A. Pregnane progestin contraception in systemic lupus erythematosus: a longitudinal study of 187 patients. Contraception. 2011;83:229–37.

    Article  CAS  PubMed  Google Scholar 

  34. Ansar Ahmed S, Young PR, Penhale WJ. The effects of female sex steroids on the development of autoimmune thyroiditis in thymectomized and irradiated rats. Clin Exp Immunol. 1983;54:351–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Strieder TG, Prummel MF, Tijssen JG, Endert E, Wiersinga WM. Risk factors for and prevalence of thyroid disorders in a cross-sectional study among healthy female relatives of patients with autoimmune thyroid disease. Clin Endocrinol (Oxf). 2003;59:396–401.

    Article  Google Scholar 

  36. Itsekson AM, Seidman DS, Zolti M, Alesker M, Carp HJ. Steroid hormone hypersensitivity: clinical presentation and management. Fertil Steril. 2011;95:2571–3.

    Article  CAS  PubMed  Google Scholar 

  37. M, AA, Ian C. Autoimmune progesterone dermatitis, Chapter 19 in Ed. Mark L et al. Treatment of Skin Disease : Comprehensive Therapeutic Strategies, Elsevier-Saunders, 2014.

    Google Scholar 

  38. Magen E, Feldman V. Autoimmune progesterone anaphylaxis in a 24 year old woman. Isr Med Assoc J. 2012;14:518–9.

    PubMed  Google Scholar 

  39. Snyder JL, Krishnaswamy G. Autoimmune progesterone dermatitis and its manifestation as anaphylaxis: a case report and literature review. Ann Allergy Asthma Immunol. 2003;90:469–77. quiz 477, 571.

    Article  PubMed  Google Scholar 

  40. Baptist, A. P., and J. L. Baldwin, 2004, Autoimmune progesterone dermatitis in a patient with endometriosis: case report and review of the literature: Clin Mol Allergy, v. 2, p. 10.

    Google Scholar 

  41. Stranahan D, Rausch D, Deng A, Gaspari A. The role of intradermal skin testing and patch testing in the diagnosis of autoimmune progesterone dermatitis. Dermatitis. 2006;17:39–42.

    Article  PubMed  Google Scholar 

  42. Prieto-Garcia A, Sloane DE, Gargiulo AR, Feldweg AM, Castells M. Autoimmune progesterone dermatitis: clinical presentation and management with progesterone desensitization for successful in vitro fertilization. Fertil Steril. 2011;95:1121.e9–13.

    Google Scholar 

  43. Itsekson AM, Soriano D, Zolti M, Seidman DS, Carp HJ. Intradermal sex hormone desensitization for relief of premenstrual symptoms may improve the obstetric outcome of women with recurrent pregnancy loss. Gynecol Endocrinol. 2013;29:169–72.

    Article  PubMed  Google Scholar 

  44. Medeiros S, Rodrigues-Alves R, Costa M, Afonso A, Rodrigues A, Cardoso J. Autoimmune progesterone dermatitis: treatment with oophorectomy. Clin Exp Dermatol. 2010;35:e12–3.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Abraham Tsur M.D. .

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Tsur, A., Hughes, G.C., Shoenfeld, Y. (2015). Progestogens and Autoimmunity. In: Carp, H. (eds) Progestogens in Obstetrics and Gynecology. Springer, Cham. https://doi.org/10.1007/978-3-319-14385-9_13

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