Following are Excerpts from the Peer-Reviewed Research Article

  Worldwide, the use of hormonal contraceptives is on the rise as a primary intervention for improving women’s health outcomes through reduced maternal mortality and increased childhood survival. There are many hormone contraceptive formulations, all of which contain some form of progesterone. Although the effects of hormone contraceptives and progesterone, specifically, have been evaluated in the context of infections of the reproductive tract, the effects of progesterone at other mucosal sites, including the respiratory tract have not been systematically evaluated. We have made the novel observation that administration of progesterone to female mice depleted of progesterone confers protection against both lethal and sublethal influenza A virus infection. In particular, progesterone reduces pulmonary inflammation, improves lung function, repairs the damaged lung epithelium, and promotes faster recovery following influenza A virus infection. Progesterone causes protection against severe outcome from influenza by inducing production of the epidermal growth factor, amphiregulin, by respiratory epithelial cells. This study provides insight into a novel mechanistic role of progesterone in the lungs and illustrates that sex hormone exposure, including through the use of hormonal contraceptives, has significant health effects beyond the reproductive tract. Natural Progesterone (P4) produced by the ovaries during reproductive cycles, or synthetic Progesterone analogues found in contraceptives (progestins), signal primarily through progesterone receptors present on many cells in the body, including immune cells (e.g., NK cells, macrophages, dendritic cells (DCs), and T cells) as well as non-immune cells, such as epithelial cells, endothelial cells, and neuronal cells. Studies show that Progesterone can alter the immune environment and promote homeostasis by decreasing inflammation and inducing anti-inflammatory responses. For example, in the presence of Progesterone, macrophages and dendritic cells have a lower state of activation, produce higher levels of anti-inflammatory cytokines, such as IL-10, and produce lower amounts of pro-inflammatory cytokines, such as IL-1β and TNF-α…

*Progesterone limits lung pathology and protects female mice against lethal Influenza A Virus infection

*Progesterone promotes a repair environment in the lungs during lethal Influenza A Virus infection

*Progesterone accelerates long-term pulmonary recovery during sub-lethal Influenza A Virus infection

*Progesterone accelerates wound healing and increases production of AREG by respiratory epithelial cells

Review the Peer-Reviewed Article Here

 

References for this Research Article

  1. Model List of Essential Medicines [Internet]. 2015 [cited April 2015]. Available from: http://www.who.int/selection_medicines/committees/expert/20/EML_2015_FINAL_amended_AUG2015.pdf?ua=1. 2. United Nations DoEaSA Population Division. Trends in Contraceptive Use Worldwide 2015. United Nations, 2015 Contract No.: ST/ESA/SER.A/349. 3. Petitti DB. Clinical practice. Combination estrogen-progestin oral contraceptives. N Engl J Med. 2003;349(15):1443–50. View Article  Google Scholar 4. Teilmann SC, Clement CA, Thorup J, Byskov AG, Christensen ST. Expression and localization of the progesterone receptor in mouse and human reproductive organs. J Endocrinol. 2006;191(3):525–35. Epub 2006/12/16. pmid:17170211. View Article PubMed/NCBI  Google Scholar 5. Jain R, Ray JM, Pan JH, Brody SL. Sex hormone-dependent regulation of cilia beat frequency in airway epithelium. Am J Respir Cell Mol Biol. 2012;46(4):446–53. Epub 2011/10/29. pmid:22033264; PubMed Central PMCID: PMC3359952. View Article PubMed/NCBI Google Scholar 6. Butts CL, Shukair SA, Duncan KM, Bowers E, Horn C, Belyavskaya E, et al. Progesterone inhibits mature rat dendritic cells in a receptor-mediated fashion. Int Immunol. 2007;19(3):287–96. pmid:17289656. View Article PubMed/NCBI Google Scholar 7. Jones LA, Kreem S, Shweash M, Paul A, Alexander J, Roberts CW. Differential modulation of TLR3- and TLR4-mediated dendritic cell maturation and function by progesterone. J Immunol. 2010;185(8):4525–34. Epub 2010/09/17. pmid:20844199.View Article PubMed/NCBI Google Scholar 8. Mao G, Wang J, Kang Y, Tai P, Wen J, Zou Q, et al. Progesterone increases systemic and local uterine proportions of CD4+CD25+ Treg cells during midterm pregnancy in mice. Endocrinology. 2010;151(11):5477–88. Epub 2010/09/17. pmid:20844003. View Article PubMed/NCBI Google Scholar 9. Lee JH, Ulrich B, Cho J, Park J, Kim CH. Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J Immunol. 2011;187(4):1778–87. Epub 2011/07/20. pmid:21768398; PubMed Central PMCID: PMC3155957.View Article PubMed/NCBI Google Scholar 10. Kaushic C, Roth KL, 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(2):204–9. pmid:21296427. View Article PubMed/NCBI Google Scholar 11. Ngcapu S, Masson L, Sibeko S, Werner L, McKinnon LR, Mlisana K, et al. Lower concentrations of chemotactic cytokines and soluble innate factors in the lower female genital tract associated with the use of injectable hormonal contraceptive. J Reprod Immunol. 2015;110:14–21. pmid:25956139. View Article PubMed/NCBI Google Scholar 12. Quispe Calla NE, Vicetti Miguel RD, Boyaka PN, Hall-Stoodley L, Kaur B, Trout W, et al. Medroxyprogesterone acetate and levonorgestrel increase genital mucosal permeability and enhance susceptibility to genital herpes simplex virus type 2 infection. Mucosal Immunol. 2016. pmid:27007679. View Article PubMed/NCBI Google Scholar 13. Braciale TJ, Sun J, Kim TS. Regulating the adaptive immune response to respiratory virus infection. Nat Rev Immunol. 2012;12(4):295–305. Epub 2012/03/10. nri3166 [pii] pmid:22402670; PubMed Central PMCID: PMC3364025. View Article PubMed/NCBI Google Scholar 14. McGill J, Van Rooijen N, Legge KL. Protective influenza-specific CD8 T cell responses require interactions with dendritic cells in the lungs. J Exp Med. 2008;205(7):1635–46. pmid:18591411. View Article PubMed/NCBI Google Scholar 15. McKinstry KK, Strutt TM, Kuang Y, Brown DM, Sell S, Dutton RW, et al. Memory CD4+ T cells protect against influenza through multiple synergizing mechanisms. J Clin Invest. 2012;122(8):2847–56. pmid:22820287; PubMed Central PMCID: PMC3408751. View Article PubMed/NCBI Google Scholar 16. Damjanovic D, Small CL, Jeyanathan M, McCormick S, Xing Z. Immunopathology in influenza virus infection: uncoupling the friend from foe. Clin Immunol. 2012;144(1):57–69. Epub 2012/06/08. pmid:22673491. View Article PubMed/NCBI Google Scholar 17. Gorski SA, Hufford MM, Braciale TJ. Recent insights into pulmonary repair following virus-induced inflammation of the respiratory tract. Curr Opin Virol. 2012;2(3):233–41. pmid:22608464; PubMed Central PMCID: PMC3378727. View Article PubMed/NCBI Google Scholar 18. Monticelli LA, Sonnenberg GF, Abt MC, Alenghat T, Ziegler CG, Doering TA, et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol. 2011;12(11):1045–54. PubMed Central PMCID: PMC3320042. View Article Google Scholar 19. Arpaia N, Green JA, Moltedo B, Arvey A, Hemmers S, Yuan S, et al. A Distinct Function of Regulatory T Cells in Tissue Protection. Cell. 2015;162(5):1078–89. pmid:26317471. View Article PubMed/NCBI Google Scholar 20. Monticelli LA, Osborne LC, Noti M, Tran SV, Zaiss DM, Artis D. IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions. Proc Natl Acad Sci U S A. 2015;112(34):10762–7. pmid:26243875; PubMed Central PMCID: PMC4553775. View Article PubMed/NCBI Google Scholar 21. Zaiss DM, Yang L, Shah PR, Kobie JJ, Urban JF, Mosmann TR. Amphiregulin, a TH2 cytokine enhancing resistance to nematodes. Science. 2006;314(5806):1746. pmid:17170297. View Article PubMed/NCBI Google Scholar 22. Aupperlee MD, Leipprandt JR, Bennett JM, Schwartz RC, Haslam SZ. Amphiregulin mediates progesterone-induced mammary ductal development during puberty. Breast cancer research: BCR. 2013;15(3):R44. pmid:23705924; PubMed Central PMCID: PMC3738150. View Article PubMed/NCBI Google Scholar 23. Das SK, Chakraborty I, Paria BC, Wang XN, Plowman G, Dey SK. Amphiregulin is an implantation-specific and progesterone-regulated gene in the mouse uterus. Mol Endocrinol. 1995;9(6):691–705. pmid:8592515. View Article PubMed/NCBI Google Scholar 24. Zaiss DM, Gause WC, Osborne LC, Artis D. Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity. 2015;42(2):216–26. pmid:25692699. View Article PubMed/NCBI Google Scholar 25. Robinson DP, Lorenzo ME, Jian W, Klein SL. Elevated 17beta-estradiol protects females from influenza a virus pathogenesis by suppressing inflammatory responses. PLoS Pathog. 2011;7(7):e1002149. Epub 2011/08/11. [pii]. pmid:21829352; PubMed Central PMCID: PMC3145801. View Article PubMed/NCBI Google Scholar 26. Larcombe AN, Foong RE, Bozanich EM, Berry LJ, Garratt LW, Gualano RC, et al. Sexual dimorphism in lung function responses to acute influenza A infection. Influenza Other Respir Viruses. 2011;5(5):334–42. Epub 2011/06/15. pmid:21668688. View Article PubMed/NCBI Google Scholar 27. Klein SL, Hodgson A, Robinson DP. Mechanisms of sex disparities in influenza pathogenesis. J Leukoc Biol. 2012;92(1):67–73. Epub 2011/12/02. pmid:22131346. View Article PubMed/NCBI Google Scholar 28. Whitacre CC. Sex differences in autoimmune disease. Nat Immunol. 2001;2(9):777–80. pmid:11526384. View Article PubMed/NCBI Google Scholar 29. Giatti S, Caruso D, Boraso M, Abbiati F, Ballarini E, Calabrese D, et al. Neuroprotective effects of progesterone in chronic experimental autoimmune encephalomyelitis. J Neuroendocrinol. 2012;24(6):851–61. Epub 2012/01/31. pmid:22283602. View Article PubMed/NCBI Google Scholar 30. Hughes GC, Choubey D. Modulation of autoimmune rheumatic diseases by oestrogen and progesterone. Nat Rev Rheumatol. 2014;10(12):740–51. pmid:25155581. View Article PubMed/NCBI Google Scholar 31. Voskuhl RR, Wang H, Wu TC, Sicotte NL, Nakamura K, Kurth F, et al. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(1):35–46. pmid:26621682. View Article PubMed/NCBI Google Scholar 32. Finch CE, Holinka CF. Aging and uterine growth during implantation in C57BL/6J mice. Exp Gerontol. 1982;17(3):235–41. pmid:7140864. View Article PubMed/NCBI Google Scholar 33. Flurkey K, Gee DM, Sinha YN, Wisner JR Jr., Finch CE. Age effects on luteinizing hormone, progesterone and prolactin in proestrous and acyclic C57BL/6j mice. Biol Reprod. 1982;26(5):835–46. pmid:7201329. View Article PubMed/NCBI Google Scholar 34. Raberg L, Sim D, Read AF. Disentangling genetic variation for resistance and tolerance to infectious diseases in animals. Science. 2007;318(5851):812–4. Epub 2007/11/03. pmid:17975068. View Article PubMed/NCBI Google Scholar 35. Topham DJ, Tripp RA, Doherty PC. CD8+ T cells clear influenza virus by perforin or Fas-dependent processes. J Immunol. 1997;159(11):5197–200. pmid:9548456. View Article PubMed/NCBI Google Scholar 36. Lawrence CW, Braciale TJ. Activation, differentiation, and migration of naive virus-specific CD8+ T cells during pulmonary influenza virus infection. J Immunol. 2004;173(2):1209–18. pmid:15240712. View Article PubMed/NCBI Google Scholar 37. de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med. 2006;12(10):1203–7. Epub 2006/09/12. nm1477 [pii] pmid:16964257. View Article PubMed/NCBI Google Scholar 38. Maloy KJ, Kullberg MC. IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol. 2008;1(5):339–49. pmid:19079198. View Article PubMed/NCBI Google Scholar 39. Weaver CT, Elson CO, Fouser LA, Kolls JK. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu Rev Pathol. 2013;8:477–512. pmid:23157335; PubMed Central PMCID: PMC3965671. View Article PubMed/NCBI Google Scholar 40. Chalmin F, Mignot G, Bruchard M, Chevriaux A, Vegran F, Hichami A, et al. Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression. Immunity. 2012;36(3):362–73. pmid:22406269. View Article PubMed/NCBI Google Scholar 41. Longhi MS, Moss A, Bai A, Wu Y, Huang H, Cheifetz A, et al. Characterization of human CD39+ Th17 cells with suppressor activity and modulation in inflammatory bowel disease. PLoS One. 2014;9(2):e87956. pmid:24505337; PubMed Central PMCID: PMC3914873. View Article PubMed/NCBI Google Scholar 42. Luetteke NC, Qiu TH, Fenton SE, Troyer KL, Riedel RF, Chang A, et al. Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development. Development. 1999;126(12):2739–50. pmid:10331984. View Article PubMed/NCBI Google Scholar 43. Pociask DA, Scheller EV, Mandalapu S, McHugh KJ, Enelow RI, Fattman CL, et al. IL-22 is essential for lung epithelial repair following influenza infection. Am J Pathol. 2013;182(4):1286–96. pmid:23490254; PubMed Central PMCID: PMC3620404. View Article PubMed/NCBI Google Scholar 44. Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care. 2008;12(2):R61. pmid:18447940; PubMed Central PMCID: PMC2447617. View Article PubMed/NCBI Google Scholar 45. Cutini PH, Campelo AE, Massheimer VL. Differential regulation of endothelium behavior by progesterone and medroxyprogesterone acetate. J Endocrinol. 2014;220(3):179–93. pmid:24301615. View Article PubMed/NCBI Google Scholar 46. Schumacher M, Hussain R, Gago N, Oudinet JP, Mattern C, Ghoumari AM. Progesterone synthesis in the nervous system: implications for myelination and myelin repair. Frontiers in neuroscience. 2012;6:10. Epub 2012/02/22. pmid:22347156; PubMed Central PMCID: PMC3274763. View Article PubMed/NCBI Google Scholar 47. Enomoto Y, Orihara K, Takamasu T, Matsuda A, Gon Y, Saito H, et al. Tissue remodeling induced by hypersecreted epidermal growth factor and amphiregulin in the airway after an acute asthma attack. J Allergy Clin Immunol. 2009;124(5):913–20 e1–7. pmid:19895983. View Article PubMed/NCBI Google Scholar 48. Fukumoto J, Harada C, Kawaguchi T, Suetsugu S, Maeyama T, Inoshima I, et al. Amphiregulin attenuates bleomycin-induced pneumopathy in mice. Am J Physiol Lung Cell Mol Physiol. 2010;298(2):L131–8. pmid:19915156. View Article PubMed/NCBI Google Scholar 49. Berasain C, Avila MA. Amphiregulin. Semin Cell Dev Biol. 2014;28:31–41. pmid:24463227. View Article PubMed/NCBI Google Scholar 50. Kelly FL, Sun J, Fischer BM, Voynow JA, Kummarapurugu AB, Zhang HL, et al. Diacetyl induces amphiregulin shedding in pulmonary epithelial cells and in experimental bronchiolitis obliterans. Am J Respir Cell Mol Biol. 2014;51(4):568–74. pmid:24816162; PubMed Central PMCID: PMC4189481. View Article PubMed/NCBI Google Scholar 51. Areia A, Vale-Pereira S, Alves V, Rodrigues-Santos P, Moura P, Mota-Pinto A. Membrane progesterone receptors in human regulatory T cells: a reality in pregnancy. BJOG. 2015;122(11):1544–50. pmid:25639501. View Article PubMed/NCBI Google Scholar 52. Moser EK, Hufford MM, Braciale TJ. Late engagement of CD86 after influenza virus clearance promotes recovery in a FoxP3+ regulatory T cell dependent manner. PLoS Pathog. 2014;10(8):e1004315. pmid:25144228; PubMed Central PMCID: PMC4140856. View Article PubMed/NCBI Google Scholar 53. Kaore SN, Langade DK, Yadav VK, Sharma P, Thawani VR, Sharma R. Novel actions of progesterone: what we know today and what will be the scenario in the future? The Journal of pharmacy and pharmacology. 2012;64(8):1040–62. Epub 2012/07/11. pmid:22775208. View Article PubMed/NCBI Google Scholar 54. Ye J, Sorrell EM, Cai Y, Shao H, Xu K, Pena L, et al. Variations in the hemagglutinin of the 2009 H1N1 pandemic virus: potential for strains with altered virulence phenotype? PLoS Pathog. 2010;6(10):e1001145. pmid:20976194; PubMed Central PMCID: PMC2954835. View Article PubMed/NCBI Google Scholar 55. Buchweitz JP, Harkema JR, Kaminski NE. Time-dependent airway epithelial and inflammatory cell responses induced by influenza virus A/PR/8/34 in C57BL/6 mice. Toxicol Pathol. 2007;35(3):424–35. Epub 2007/05/10. 778353367 [pii] pmid:17487773. View Article PubMed/NCBI Google Scholar 56. Tate MD, Pickett DL, van Rooijen N, Brooks AG, Reading PC. Critical role of airway macrophages in modulating disease severity during influenza virus infection of mice. J Virol. 2010;84(15):7569–80. Epub 2010/05/28. JVI.00291-10 [pii] pmid:20504924; PubMed Central PMCID: PMC2897615. View Article PubMed/NCBI Google Scholar 57. Limjunyawong N, Fallica J, Ramakrishnan A, Datta K, Gabrielson M, Horton M, et al. Phenotyping mouse pulmonary function in vivo with the lung diffusing capacity. J Vis Exp. 2015;(95):e52216. pmid:25590416. View Article PubMed/NCBI Google Scholar 58. Shang Y, Das S, Rabold R, Sham JS, Mitzner W, Tang WY. Epigenetic alterations by DNA methylation in house dust mite-induced airway hyperresponsiveness. Am J Respir Cell Mol Biol. 2013;49(2):279–87. pmid:23526225; PubMed Central PMCID: PMC3824034. View Article PubMed/NCBI Google Scholar 59. You Y, Richer EJ, Huang T, Brody SL. Growth and differentiation of mouse tracheal epithelial cells: selection of a proliferative population. Am J Physiol Lung Cell Mol Physiol. 2002;283(6):L1315–21. Epub 2002/10/22. View Article Google Scholar 60. Rowe RK, Brody SL, Pekosz A. Differentiated cultures of primary hamster tracheal airway epithelial cells. In Vitro Cell Dev Biol Anim. 2004;40(10):303–11. Epub 2005/03/23. 0408056 [pii] pmid:15780007; PubMed Central PMCID: PMC1592688. View Article PubMed/NCBI Google Scholar