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Progestogens and Autoimmunity

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Progestogens in Obstetrics and Gynecology

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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. However, female sex hormones influence immunity and autoimmunity in very different ways: estrogens generally enhance the immune system and increase susceptibility to autoimmunity, while progestogens may be immunosuppressive and protect against autoimmunity.

Progesterone immunomodulation during pregnancy is of special interest. One of the challenges of pregnancy is to prevent maternal infections while protecting the fetus from potentially harmful maternal immune responses. Progesterone’s immunomodulatory effects may be crucial in balancing these opposing requirements.

Progesterone enhances Th2 and Treg activity while decreasing Th1 and Th17 activity. These actions likely contribute to the remission of Th1-mediated and Th17-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis during the high progesterone state of pregnancy. Accordingly, progestogens may serve as potential treatments for these diseases.

Another aspect of the interaction of progestogens with the immune system is progestogen hypersensitivity. This rare condition is characterized by a hypersensitive reaction to endogenous progesterone 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. Rubtsova K, Marrack P, Rubtsov AV. Sexual dimorphism in autoimmunity. J Clin Invest. 2015;125:2187–93. https://doi.org/10.1172/JCI78082.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Fairweather D, Frisancho-Kiss S, Rose NR. Sex differences in autoimmune disease from a pathological perspective. Am J Pathol. 2008;173:600–9. https://doi.org/10.2353/ajpath.2008.071008.

    Article  CAS  PubMed  PubMed Central  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. https://doi.org/10.1016/j.jaut.2011.10.003.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  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. https://doi.org/10.1111/j.1398-9995.2008.01880.x.

    Article  CAS  PubMed  Google Scholar 

  6. Bouman A, Heineman MJ, Faas MM. Sex hormones and the immune response in humans. Hum Reprod Update. 2005;11:411–23. https://doi.org/10.1093/humupd/dmi008.

    Article  CAS  PubMed  Google Scholar 

  7. Hughes GC, Choubey D. Modulation of autoimmune rheumatic diseases by oestrogen and progesterone. Nat Rev Rheumatol. 2014;10:740–51. https://doi.org/10.1038/nrrheum.2014.144.

    Article  CAS  PubMed  Google Scholar 

  8. Scofield RH. Genetics of systemic lupus erythematosus and Sjögren’s syndrome. Curr Opin Rheumatol. 2009;21:448–53. https://doi.org/10.1097/BOR.0b013e32832f0861.

    Article  CAS  PubMed  Google Scholar 

  9. Bellott DW, et al. Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators. Nature. 2014;508:494–9. https://doi.org/10.1038/nature13206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Adams KM, Nelson JL. Microchimerism: an investigative frontier in autoimmunity and transplantation. JAMA. 2004;291:1127–31. https://doi.org/10.1001/jama.291.9.1127.

    Article  CAS  PubMed  Google Scholar 

  11. Szekeres-Bartho J, Szekeres G, Debre P, Autran B, Chaouat G. Reactivity of lymphocytes to a progesterone receptor-specific monoclonal antibody. Cell Immunol. 1990;125:273–83. https://doi.org/10.1016/0008-8749(90)90083-4.

    Article  CAS  PubMed  Google Scholar 

  12. Dosiou C, et al. Expression of membrane progesterone receptors on human T lymphocytes and Jurkat cells and activation of G-proteins by progesterone. J Endocrinol. 2008;196:67–77. https://doi.org/10.1677/JOE-07-0317.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Ostensen M, Villiger PM. The remission of rheumatoid arthritis during pregnancy. Semin. Immunopathol. 2007;29:185–91. https://doi.org/10.1007/s00281-007-0072-5.

    Article  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Hughes GC, Thomas S, Li C, Kaja MK, Clark EA. Cutting edge: progesterone regulates IFN-alpha production by plasmacytoid dendritic cells. J Immunol. 2008;180:2029–33. https://doi.org/10.4049/jimmunol.180.4.2029.

    Article  CAS  PubMed  Google Scholar 

  17. 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  CAS  Google Scholar 

  18. Gargano J, et al. Mid-pregnancy circulating cytokine levels, histologic chorioamnionitis and spontaneous preterm birth. J Reprod Immunol. 2008;79:100–10.

    Article  CAS  Google Scholar 

  19. Moura E, et al. Inflammatory cytokine gene polymorphisms and spontaneous preterm birth. J Reprod Immunol. 2009;80:41–8.

    Article  Google Scholar 

  20. Miossec P, Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov. 2012;11:763–76. https://doi.org/10.1038/nrd3794.

    Article  CAS  PubMed  Google Scholar 

  21. 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. https://doi.org/10.1111/j.1600-0897.2012.01116.x.

    Article  CAS  PubMed  Google Scholar 

  22. Hughes GC. Progesterone and autoimmune disease. Autoimmun Rev. 2012;11:A502–14. https://doi.org/10.1016/j.autrev.2011.12.003.

    Article  CAS  PubMed  Google Scholar 

  23. Arck PC, Hecher K. Fetomaternal immune cross-talk and its consequences for maternal and offspring’s health. Nat Med. 2013;19:548–56. https://doi.org/10.1038/nm.3160.

    Article  CAS  PubMed  Google Scholar 

  24. 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 

  25. 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. https://doi.org/10.1016/j.chom.2011.06.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sakiani S, Olsen NJ, Kovacs WJ. Gonadal steroids and humoral immunity. Nat Rev Endocrinol. 2013;9:56–62. https://doi.org/10.1038/nrendo.2012.206.

    Article  CAS  PubMed  Google Scholar 

  27. Wong AH, Agrawal N, Hughes GC. Altered IgG autoantibody levels and CD4(+) T cell subsets in lupus-prone Nba2 mice lacking the nuclear progesterone receptor. Autoimmunity. 2015;48:389–401. https://doi.org/10.3109/08916934.2015.1030613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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. https://doi.org/10.1146/annurev.immunol.25.022106.141702.

    Article  CAS  PubMed  Google Scholar 

  29. 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. https://doi.org/10.1016/j.imlet.2011.01.017.

    Article  CAS  PubMed  Google Scholar 

  30. 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. https://doi.org/10.1002/art.24003.

    Article  PubMed  Google Scholar 

  31. Østensen M, Villiger PM, Förger F. Interaction of pregnancy and autoimmune rheumatic disease. Autoimmun Rev. 2012;11:A437–46. https://doi.org/10.1016/j.autrev.2011.11.013.

    Article  CAS  PubMed  Google Scholar 

  32. Jethwa H, Lam S, Smith C, Giles I. Does rheumatoid arthritis really improve during pregnancy? a systematic review and metaanalysis. J Rheumatol. 2019;46:245–50. https://doi.org/10.3899/jrheum.180226.

    Article  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  34. De Man YA, et al. 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. https://doi.org/10.1136/ard.2008.104331.

    Article  CAS  PubMed  Google Scholar 

  35. Houtchens M. Multiple sclerosis and pregnancy. Clin Obstet Gynecol. 2013;56:342–9. https://doi.org/10.1097/GRF.0b013e31828f272b.

    Article  PubMed  Google Scholar 

  36. Schumacher M, et al. Progesterone synthesis in the nervous system: implications for myelination and myelin repair. Front Neurosci. 2012;6:10. https://doi.org/10.3389/fnins.2012.00010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Vukusic S, et al. 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. https://doi.org/10.1016/j.jns.2009.08.056.

    Article  CAS  PubMed  Google Scholar 

  38. Bansal AS, et al. Mechanism of human chorionic gonadotrophin-mediated immunomodulation in pregnancy. Expert Rev Clin Immunol. 2012;8:747–53. https://doi.org/10.1586/eci.12.77.

    Article  CAS  PubMed  Google Scholar 

  39. Petri M. Prospective study of systemic lupus erythematosus pregnancies. Lupus. 2004;13:688–9. https://doi.org/10.1191/0961203303lu2006oa.

    Article  CAS  PubMed  Google Scholar 

  40. Kwok LW, Tam LS, Zhu T, Leung YY, Li E. Predictors of maternal and fetal outcomes in pregnancies of patients with systemic lupus erythematosus. Lupus. 2011;20:829–36. https://doi.org/10.1177/0961203310397967.

    Article  PubMed  Google Scholar 

  41. Smyth A, et al. A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis. Clin J Am Soc Nephrol. 2010;5:2060–8. https://doi.org/10.2215/CJN.00240110.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Petri M. Pregnancy and systemic lupus erythematosus. Best Pract Res Clin Obstet Gynaecol. 2019;64:24–30. https://doi.org/10.1016/j.bpobgyn.2019.09.002.

    Article  PubMed  Google Scholar 

  43. Hughes GC, et al. Decrease in glomerulonephritis and Th1-associated autoantibody production after progesterone treatment in NZB/NZW mice. Arthritis Rheum. 2009;60:1775–84. https://doi.org/10.1002/art.24548.

    Article  CAS  PubMed  Google Scholar 

  44. Chabbert-Buffet N, et al. Pregnane progestin contraception in systemic lupus erythematosus: a longitudinal study of 187 patients. Contraception. 2011;83:229–37. https://doi.org/10.1016/j.contraception.2010.08.012.

    Article  CAS  PubMed  Google Scholar 

  45. Petri M, et al. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med. 2005;353:2550–8. https://doi.org/10.1056/NEJMoa051135.

    Article  CAS  PubMed  Google Scholar 

  46. Sánchez-Guerrero J, et al. A trial of contraceptive methods in women with systemic lupus erythematosus. N Engl J Med. 2005;353:2539–49. https://doi.org/10.1056/NEJMoa050817.

    Article  PubMed  Google Scholar 

  47. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 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. 2003;59:396–401.

    Article  Google Scholar 

  49. Romero R, et al. Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data. Am J Obstet Gynecol. 2018;218:161–80. https://doi.org/10.1016/j.ajog.2017.11.576.

    Article  CAS  PubMed  Google Scholar 

  50. Tsur A, Hughes GC, Shoenfeld Y, Carp H. Interdisciplinary exchange of ideas: progestagens for autoimmunity, biologics for pregnancy complications. Immunol Res. 2015;61:31–4. https://doi.org/10.1007/s12026-014-8621-1.

    Article  CAS  PubMed  Google Scholar 

  51. 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. https://doi.org/10.1016/S1081-1206(10)61838-8.

    Article  PubMed  Google Scholar 

  52. Itsekson AM, Seidman DS, Zolti M, Alesker M, Carp HJ. Steroid hormone hypersensitivity: clinical presentation and management. Fertil Steril. 2011;95:2571–3. https://doi.org/10.1016/j.fertnstert.2011.05.025.

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  54. Lebwohl MG, Ian C. In: Lebwohl Mark G, Heymann Warren R, Berth-Jones J, Ian C, editors. Treatment of skin disease: comprehensive therapeutic strategies. Amsterdam: Elsevier; 2014.

    Google Scholar 

  55. Kanninen TT, Moretti ML, Lakhi NA. Autoimmune progesterone dermatitis following vaginal progesterone exposure in pregnancy. Obstet Med. 2019;12:100–2. https://doi.org/10.1177/1753495X18771255.

    Article  PubMed  Google Scholar 

  56. Baptist AP, Baldwin JL. Autoimmune progesterone dermatitis in a patient with endometriosis: case report and review of the literature. Clin Mol Allergy. 2004;2:10. https://doi.org/10.1186/1476-7961-2-10.

    Article  PubMed  PubMed Central  Google Scholar 

  57. 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  Google Scholar 

  58. 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. https://doi.org/10.1016/j.fertnstert.2010.10.038.

    Article  PubMed  Google Scholar 

  59. 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. https://doi.org/10.3109/09513590.2012.730582.

    Article  PubMed  Google Scholar 

  60. Medeiros S, et al. Autoimmune progesterone dermatitis: treatment with oophorectomy. Clin Exp Dermatol. 2010;35:e12–3. https://doi.org/10.1111/j.1365-2230.2009.03217.x.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, The Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel

    Abraham Tsur

  2. School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Abraham Tsur & Yehuda Shoenfeld

  3. Stanford University School of Medicine, Stanford, CA, USA

    Abraham Tsur

  4. Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA

    Grant C. Hughes

  5. Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel

    Yehuda Shoenfeld

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  1. Abraham Tsur
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  2. Grant C. Hughes
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  3. Yehuda Shoenfeld
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Correspondence to Abraham Tsur .

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Editors and Affiliations

  1. Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Howard J.A. Carp

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Tsur, A., Hughes, G.C., Shoenfeld, Y. (2021). Progestogens and Autoimmunity. In: Carp, H.J. (eds) Progestogens in Obstetrics and Gynecology. Springer, Cham. https://doi.org/10.1007/978-3-030-52508-8_13

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