Review Article | Published:

The role of sex hormones in immune protection of the female reproductive tract

Nature Reviews Immunology volume 15, pages 217230 (2015) | Download Citation

Abstract

Within the human female reproductive tract (FRT), the challenge of protection against sexually transmitted infections (STIs) is coupled with the need to enable successful reproduction. Oestradiol and progesterone, which are secreted during the menstrual cycle, affect epithelial cells, fibroblasts and immune cells in the FRT to modify their functions and hence the individual's susceptibility to STIs in ways that are unique to specific sites in the FRT. The innate and adaptive immune systems are under hormonal control, and immune protection in the FRT varies with the phase of the menstrual cycle. Immune protection is dampened during the secretory phase of the cycle to optimize conditions for fertilization and pregnancy, which creates a 'window of vulnerability' during which potential pathogens can enter and infect the FRT.

Key points

  • Interactions between the innate and adaptive immune systems and the endocrine system in the female reproductive tract (FRT) are essential for successful reproduction and for maintaining immune protection against sexually transmitted infections.

  • Epithelial cells, fibroblasts and immune cells throughout the FRT contribute to immune protection and create a mucosal environment that supports reproduction.

  • Immune cell number, tissue distribution, phenotype and function throughout the menstrual cycle are site-specific in the lower and upper FRT and are differentially regulated by sex hormones. Hormonal regulation of immune cells in the endometrium is required to prevent sperm rejection and to prepare the endometrial tissue for implantation.

  • Epithelial cells, fibroblasts and immune cells at each site are hormonally regulated and influence one another through the secretion of growth factors, cytokines, chemokines and antimicrobial factors.

  • Immune protection that is regulated by oestradiol and progesterone is characterized by phenotypic changes to cells, including alterations to the secretion of cytokines, chemokines and antimicrobial factors, receptor expression, barrier function, cellular responses to pathogens, and the distribution and function of immune cells.

  • Immune regulation to achieve optimal conditions for fertilization, implantation and pregnancy creates a 'window of vulnerability' during the secretory phase of the menstrual cycle, such that HIV and possibly other sexually transmitted pathogens are able to breach and infect the FRT.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    World Health Organization. Progress Report 2011: Global HIV/AIDS Response (WHO, 2011).

  2. 2.

    World Health Organization. Prevalance and Incidence of Selected Sexually Transmitted Infections (WHO, 2011).

  3. 3.

    & A new strategy to understand how HIV infects women: identification of a window of vulnerability during the menstrual cycle. AIDS 22, 1909–1917 (2008). This paper hypothesizes the existence of a window for increased susceptibility to HIV infection during the secretory phase of the menstrual cycle, during which time components of innate, humoral and cell-mediated immunity are suppressed by sex hormones.

  4. 4.

    in Endocrine Physiology (ed. Porterfield, S. P.) 169–199 (Mosby, 2001).

  5. 5.

    et al. Flow cytometric analysis of leukocytes in the human female reproductive tract: comparison of fallopian tube, uterus, cervix, and vagina. Am. J. Reprod. Immunol. 38, 350–359 (1997). This paper is the first and most complete side-by-side comparison of leukocyte subsets across the FRT during the proliferative and secretory phases of the menstrual cycle.

  6. 6.

    et al. Genomic HIV RNA induces innate immune responses through RIG-I-dependent sensing of secondary-structured RNA. PLoS ONE 7, e29291 (2012).

  7. 7.

    et al. Chlamydial heat shock protein 60 activates macrophages and endothelial cells through Toll-like receptor 4 and MD2 in a MyD88-dependent pathway. J. Immunol. 168, 1435–1440 (2002).

  8. 8.

    et al. Toll-like receptor-2, but not Toll-like receptor-4, is essential for development of oviduct pathology in chlamydial genital tract infection. J. Immunol. 171, 6187–6197 (2003).

  9. 9.

    Recognition of viral single-stranded RNA by Toll-like receptors. Adv. Drug Deliv. Rev. 60, 813–823 (2008).

  10. 10.

    , , , & The Lip lipoprotein from Neisseria gonorrhoeae stimulates cytokine release and NF-κB activation in epithelial cells in a Toll-like receptor 2-dependent manner. J. Biol. Chem. 278, 46252–46260 (2003).

  11. 11.

    et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526–1529 (2004).

  12. 12.

    & Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J. Immunol. 168, 554–561 (2002).

  13. 13.

    et al. Differential expression of Toll-like receptors 2 and 4 in tissues of the human female reproductive tract. Infect. Immun. 72, 5799–5806 (2004).

  14. 14.

    et al. Pathogen recognition in the human female reproductive tract: expression of intracellular cytosolic sensors NOD1, NOD2, RIG-1, and MDA5 and response to HIV-1 and Neisseria gonorrhea. Am. J. Reprod. Immunol. 69, 41–51 (2013).

  15. 15.

    et al. Functional expression of pattern recognition receptors in tissues of the human female reproductive tract. J. Reprod. Immunol. 80, 33–40 (2009).

  16. 16.

    et al. Menstrual cycle-dependent changes of Toll-like receptors in endometrium. Hum. Reprod. 22, 586–593 (2007).

  17. 17.

    et al. Expression of toll-like receptors 2, 3, 4, and 9 genes in the human endometrium during the menstrual cycle. J. Reprod. Immunol. 74, 53–60 (2007).

  18. 18.

    , , , & Human endometrial epithelial cells cyclically express Toll-like receptor 3 (TLR3) and exhibit TLR3-dependent responses to dsRNA. Hum. Immunol. 66, 469–482 (2005).

  19. 19.

    , , , & Modulation of expression of Toll-like receptors in the human endometrium. Am. J. Reprod. Immunol. 61, 338–345 (2009).

  20. 20.

    & Probiotic lactobacillus and estrogen effects on vaginal epithelial gene expression responses to Candida albicans. J. Biomedi. Sci. 19, 58 (2012).

  21. 21.

    , , & IL-1β-mediated proinflammatory responses are inhibited by estradiol via down-regulation of IL-1 receptor type I in uterine epithelial cells. J. Immunol. 175, 6509–6516 (2005).

  22. 22.

    et al. Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture. Mucosal Immunol. 1, 317–325 (2008).

  23. 23.

    , , & 17β-Estradiol inhibits inflammatory gene expression by controlling NF-κB intracellular localization. Mol. Cell Biol. 25, 2957–2968 (2005).

  24. 24.

    , & Estradiol suppresses NF-κB activation through coordinated regulation of let-7a and miR-125b in primary human macrophages. J. Immunol. 184, 5029–5037 (2010).

  25. 25.

    et al. Secretory leucoprotease inhibitor binds to NF-κB binding sites in monocytes and inhibits p65 binding. J. Exp. Med. 202, 1659–1668 (2005).

  26. 26.

    et al. PRO 2000 elicits a decline in genital tract immune mediators without compromising intrinsic antimicrobial activity. AIDS 21, 467–476 (2007). This paper shows that cytokine and chemokine levels in cervico-vaginal secretions are selectively decreased at the mid-cycle stage of the menstrual cycle.

  27. 27.

    et al. Cyclic changes in the level of the innate immune molecule, surfactant protein-A, and cytokines in vaginal fluid. Am. J. Reprod. Immunol. 68, 244–250 (2012).

  28. 28.

    et al. A menstrual cycle pattern for cytokine levels exists in HIV-positive women: implication for HIV vaginal and plasma shedding. AIDS 15, 1535–1543 (2001).

  29. 29.

    et al. The impact of the ovulatory cycle on cytokine production: evaluation of systemic, cervicovaginal, and salivary compartments. J. Inter. Cyto. Res. 20, 719–724 (2000).

  30. 30.

    , , & Antimicrobial components of vaginal fluid. Am. J. Obst. Gynecol. 187, 561–568 (2002).

  31. 31.

    et al. Female genital tract secretions inhibit herpes simplex virus infection: correlation with soluble mucosal immune mediators and impact of hormonal contraception. Am. J. Reprod. Immunol. 63, 110–119 (2010).

  32. 32.

    et al. Innate immunity in the vagina (part II): anti-HIV activity and antiviral content of human vaginal secretions. Am. J. Reprod. Immunol. 72, 22–33 (2014).

  33. 33.

    et al. Cytokine profiling in endometrial secretions: a non-invasive window on endometrial receptivity. Reprod. Biomed. Online 18, 85–94 (2009).

  34. 34.

    , & Effect of oestradiol on cell proliferation and histological changes in the uterus and vagina of mice. J. Endocrinol. 49, 243–252 (1971).

  35. 35.

    & Estradiol-17β regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling. Proc. Natl Acad. Sci. USA 104, 15847–15851 (2007).

  36. 36.

    et al. Progesterone implants enhance SIV vaginal transmission and early virus load. Nature Med. 2, 1084–1089 (1996).

  37. 37.

    , & Structure and function of intercellular junctions in human cervical and vaginal mucosal epithelia. Biol. Reprod. 85, 97–104 (2011).

  38. 38.

    Aging and estrogen effects on transcervical-transvaginal epithelial permeability. J. Clin. Endocrinol. Metab. 90, 345–351 (2005).

  39. 39.

    , & Estrogen abrogates transcervical tight junctional resistance by acceleration of occludin modulation. J. Clin. Endocrinol. Metab. 89, 5145–5155 (2004).

  40. 40.

    et al. Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation. PLoS Pathog. 6, e1000852 (2010).

  41. 41.

    et al. Mucin genes expressed by human female reproductive tract epithelia. Biol. Reprod. 56, 999–1011 (1997).

  42. 42.

    , , , & Scanning electron and light microscopy study of the cervical mucus in women with polycystic ovary syndrome. J. Elect. Micro. 58, 21–27 (2009).

  43. 43.

    Functions and physical properties of mucus in the female genital tract. Brit. Med. Bull. 34, 83–88 (1978).

  44. 44.

    et al. Human cervicovaginal mucus contains an activity that hinders HIV-1 movement. Mucosal Immunol. 6, 427–434 (2013).

  45. 45.

    , , & Differential binding of IgG and IgA to mucus of the female reproductive tract. PLoS ONE 8, e76176 (2013).

  46. 46.

    , , , & Innate immunity in the human female reproductive tract: endocrine regulation of endogenous antimicrobial protection against HIV and other sexually transmitted infections. Am. J. Reprod. Immunol. 65, 196–211 (2011).

  47. 47.

    , , & Innate immunity in the vagina (part I): estradiol inhibits HBD2 and elafin secretion by human vaginal epithelial cells. Am. J. Reprod. Immunol. 69, 463–474 (2013).

  48. 48.

    et al. A role for the chemokine receptor CCR6 in mammalian sperm motility and chemotaxis. J. Cell. Physiol. 229, 68–78 (2014).

  49. 49.

    & Effect of menstrual status on antibacterial activity and secretory leukocyte protease inhibitor production by human uterine epithelial cells in culture. J. Infect. Dis. 185, 1606–1613 (2002).

  50. 50.

    , , & Uterine epithelial cells specifically induce interferon-stimulated genes in response to polyinosinic-polycytidylic acid independently of estradiol. PLoS ONE 7, e35654 (2012).

  51. 51.

    et al. Interferon-ε protects the female reproductive tract from viral and bacterial infection. Science 339, 1088–1092 (2013). This paper shows the effect of the menstrual cycle on IFNε secretion by epithelial cells in the FRT and the role of IFNε in protection against herpes simplex virus 2 and Chlamydia muridarum.

  52. 52.

    & Intestinal stromal cells in mucosal immunity and homeostasis. Mucosal Immunol. 6, 224–234 (2013).

  53. 53.

    et al. Modulation of hepatocyte growth factor secretion in human female reproductive tract stromal fibroblasts by poly(I:C) and estradiol. Am. J. Reprod. Immunol. 67, 44–53 (2012).

  54. 54.

    , , & Antiviral responses of fibroblasts in the female reproductive tract. AIDS Res. Hum. Retroviruses 30, A237–A237 (2014).

  55. 55.

    , , & Establishment of a primary culture model of mouse uterine and vaginal stroma for studying in vitro estrogen effects. Exp. Biol. Med. 231, 303–310 (2006).

  56. 56.

    & Oestrogen and progesterone regulation of inflammatory processes in the human endometrium. J. Steroid Biochem. Mol. Biol. 120, 116–126 (2010).

  57. 57.

    , , , & CD8+ T cells in human uterine endometrial lymphoid aggregates: evidence for accumulation of cells by trafficking. Immunology 102, 434–440 (2001).

  58. 58.

    & Inflammation, leukocytes and menstruation. Rev. Endocr. Metab. Disord. 13, 277–288 (2012).

  59. 59.

    , & Immunological microenvironments in the human vagina and cervix: mediators of cellular immunity are concentrated in the cervical transformation zone. Biol. Reprod. 73, 1253–1263 (2005).

  60. 60.

    et al. HIV-1 sexual transmission: early events of HIV-1 infection of human cervico-vaginal tissue in an optimized ex vivo model. Mucosal Immunol. 3, 280–290 (2010).

  61. 61.

    , , , & Phenotype and susceptibility to HIV infection of CD4 TH17 cells in the human female reproductive tract. Mucosal Immunol. 7, 1375–1385 (2014). This side-by-side comparison of TH17 cells from the endometrium, endocervix and ectocervix shows an increased presence of TH17 cells and a higher susceptibility to HIV infection in the cervix and the ectocervix compared with in the endometrium.

  62. 62.

    et al. Phenotype and functionality of CD4+ and CD8+ T cells in the upper reproductive tract of healthy premenopausal women. Am. J. Reprod. Immunol. 71, 95–108 (2014).

  63. 63.

    , & Distribution of immune cells in the human cervix and implications for HIV transmission. Am. J. Reprod. Immunol. 71, 252–264 (2014).

  64. 64.

    et al. Unique CD8+ T cell-rich lymphoid aggregates in human uterine endometrium. J. Leukoc. Biol. 61, 427–435 (1997). This study shows the menstrual cycle-dependent formation of lymphoid aggregates in the endometrium; in the absence of infection, aggregates unique to the FRT reach maximal size during the secretory phase of the cycle.

  65. 65.

    et al. Detection of intraepithelial and stromal langerin and CCR5 positive cells in the human endometrium: potential targets for HIV infection. PLoS ONE 6, e21344 (2011).

  66. 66.

    et al. Persistence of HIV-1 receptor-positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition. Nature Med. 15, 886–892 (2009).

  67. 67.

    & T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science 346, 93–98 (2014).

  68. 68.

    , , , & Innate and adaptive immunity in female genital tract: cellular responses and interactions. Immunol. Rev. 206, 306–335 (2005).

  69. 69.

    et al. Macrophage expression in endometrium of women with and without endometriosis. Hum. Reprod. 24, 325–332 (2009).

  70. 70.

    , , & Endometrial dendritic cell populations during the normal menstrual cycle. Hum. Reprod. 23, 1574–1580 (2008).

  71. 71.

    et al. Dendritic cells and B cells maximize mucosal TH1 memory response to herpes simplex virus. J. Exp. Med. 205, 3041–3052 (2008).

  72. 72.

    et al. Endometrial NK cells are special immature cells that await pregnancy. J. Immunol. 181, 1869–1876 (2008).

  73. 73.

    et al. Unique characteristics of NK cells throughout the human female reproductive tract. Clin. Immunol. 124, 69–76 (2007).

  74. 74.

    , , & Recruitment of uterine NK cells: induction of CXC chemokine ligands 10 and 11 in human endometrium by estradiol and progesterone. J. Immunol. 173, 6760–6766 (2004).

  75. 75.

    , , , & The role of inflammation for a successful implantation. Am. J. Reprod. Immunol. 72, 141–147 (2014).

  76. 76.

    Mechanisms of T cell tolerance towards the allogeneic fetus. Nature Rev. Immunol. 13, 23–33 (2013).

  77. 77.

    et al. CD3+CD8+ CTL activity within the human female reproductive tract: influence of stage of the menstrual cycle and menopause. J. Immunol. 158, 3017–3027 (1997). This is the first demonstration of sex hormone-mediated control of CD8+ CTL activity in the FRT; CTL activity is absent during the secretory phase of the menstrual cycle in the endometrium but not in the lower tract.

  78. 78.

    et al. The role of Foxp3+ regulatory T-cells in endometriosis: a potential controlling mechanism for a complex, chronic immunological condition. Hum. Reprod. 25, 900–907 (2010).

  79. 79.

    , , & Expansion of CD4+CD25+ and FOXP3+ regulatory T cells during the follicular phase of the menstrual cycle: implications for human reproduction. J. Immunol. 178, 2572–2578 (2007).

  80. 80.

    , , , & TH17 and regulatory T cells in women with recurrent pregnancy loss. Am. J. Reprod. Immunol. 67, 311–318 (2012).

  81. 81.

    et al. Estrogen deficiency induces the differentiation of IL-17 secreting TH17 cells: a new candidate in the pathogenesis of osteoporosis. PLoS ONE 7, e44552 (2012).

  82. 82.

    et al. Female sex hormones regulate the TH17 immune response to sperm and Candida albicans. Hum. Reprod. 28, 3283–3291 (2013).

  83. 83.

    , & in Mucosal Immunology (eds Mestecky, J. et al.) 1661–1678 (Academic Press, 2005).

  84. 84.

    , , & The human female reproductive tract: immunohistological localization of gA, gG, gM, secretory piece and lactoferrin. Amer. J. Obstet. Gynecol. 108, 1102–1108 (1970).

  85. 85.

    , & A study of the secretory immune system of the female genital tract. J. Obstet. Gynecol. 82, 812–816 (1975).

  86. 86.

    , & Immunoglobulins and secretory component in endometrium and cervix: influence of inflammation and carcinoma. Virch. Arch. Path. Anat. Histol. 377, 211–223 (1978).

  87. 87.

    , , , & Variations in immunoglobulins and IgA subclasses of human uterine cervical secretions around the time of ovulation. Clin. Exp. Immunol. 104, 538–542 (1996).

  88. 88.

    & The local immunological defense system of the human endometrium. J. Reprod. Immunol. 1, 39–45 (1979).

  89. 89.

    , , & Immunoglobulins, proteinase inhibitors, albumin, and lysozyme in human cervical mucus. I. Communication: hormonal profiles and cervical mucus changes—methods and results. Am. J. Obstet. Gynecol. 129, 629–636 (1977).

  90. 90.

    in The Biology of the Cervix (eds Blandau, R. J. & Moghissi, K.) 201–233 (The Univ. of Chicago Press, 1973). This is the most complete demonstration of changes in immune parameters in human cervical secretions that occur during specific stages of the menstrual cycle in women.

  91. 91.

    , & Ovarian steroid hormones: effects on immune responses and Chlamydia trachomatis infections of the female genital tract. Mucosal Immunol. 6, 859–875 (2013).

  92. 92.

    & in Mucosal Immune Defense: Immunoglobulin A (ed. Kaetzel, C.) 291–320 (Kluwer Academic/Plenum Publisher, 2008).

  93. 93.

    , , & Variations in the levels of secretory component in human uterine fluid during the menstrual cycle. J. Steroid Biochem. 20, 509–513 (1984).

  94. 94.

    , , & Secretory component production by polarized epithelial cells from the human female reproductive tract. Immunol. Invest. 27, 167–180 (1998).

  95. 95.

    , & Polymeric immunoglobulin A receptor in the rodent female reproductive tract: influence of estradiol in the vagina and differential expression of messenger ribonucleic acid during estrous cycle. Biol. Reprod. 57, 958–966 (1997).

  96. 96.

    & Origin and homing of intestinal IgA antibody-secreting cells. J. Exp. Med. 195, F5–F8 (2002).

  97. 97.

    , & Gut-associated lymphoid tissue as source of an IgA immune response in respiratory tissues after oral immunization and intrabronchial challenge. Cell. Immunol. 106, 132–138 (1987).

  98. 98.

    , , , & Origin of IgA-secreting plasma cells in the mammary gland. J. Exp. Med. 146, 1311–1322 (1977).

  99. 99.

    , & Mesenteric lymph node B lymphoblasts which home to the small intestine are precommitted to IgA synthesis. J. Exp. Med. 145, 866–875 (1977).

  100. 100.

    & Anti-bacterial IgA and IgG in mouse uterine luminal fluid, vaginal washings and serum. J. Reprod. Immunol. 13, 65–72 (1988).

  101. 101.

    et al. Human decidual NK cells from gravid uteri and NK cells from cycling endometrium are distinct NK cell subsets. Placenta 31, 334–338 (2010).

  102. 102.

    & Uterine NK cells: active regulators at the maternal-fetal interface. J. Clin. Invest. 124, 1872–1879 (2014).

  103. 103.

    , , & Unique phenotype of human uterine NK cells and their regulation by endogenous TGF-β. J. Leukoc. Biol. 76, 667–675 (2004). This study shows that the tissue environment, containing locally produced TGFβ, regulates NK cell function in the human endometrium.

  104. 104.

    et al. Identification of diverse innate lymphoid cells in human decidua. Mucosal Immunol. 8, 254–264 (2014).

  105. 105.

    et al. Innate lymphoid cells — a proposal for uniform nomenclature. Nature Rev. Immunol. 13, 145–149 (2013).

  106. 106.

    et al. A subset of human uterine endometrial macrophages is alternatively activated. Am. J. Reprod. Immunol. 68, 374–386 (2012).

  107. 107.

    et al. Macrophages in vaginal but not intestinal mucosa are monocyte-like and permissive to human immunodeficiency virus type 1 infection. J. Virol. 83, 3258–3267 (2009).

  108. 108.

    et al. Distinct characteristics of endometrial and decidual macrophages and regulation of their permissivity to HIV-1 infection by SAMHD1. J. Virol. 89, 1329–1339 (2015).

  109. 109.

    , , & Secretion of cytokines and chemokines by polarized human epithelial cells from the female reproductive tract. Hum. Reprod. 20, 1439–1446 (2005).

  110. 110.

    , , , & Toll-like receptor (TLR) expression and TLR-mediated cytokine/chemokine production by human uterine epithelial cells. Immunology 112, 428–436 (2004).

  111. 111.

    , , & Innate immunity in the human female reproductive tract: antiviral response of uterine epithelial cells to the TLR3 agonist poly(I:C). J. Immunol. 174, 992–1002 (2005).

  112. 112.

    , , & Endometrial stromal cells regulate epithelial cell growth in vitro: a new co-culture model. Hum. Reprod. 16, 836–845 (2001).

  113. 113.

    & Effect of mouse uterine stromal cells on epithelial cell transepithelial resistance (TER) and TNFα and TGFβ release in culture. Biol. Reprod. 69, 1091–1098 (2003).

  114. 114.

    , , & Regulation of interleukin-8 gene expression in human endometrial cells in culture. Mol. Cell. Endocrinol. 94, 195–204 (1993).

  115. 115.

    , , , & Regulation of monocyte chemotactic protein-1 expression in human endometrial stromal cells by estrogen and progesterone. Biol. Reprod. 61, 85–90 (1999).

  116. 116.

    , , , & Human uterine epithelial cell secretions regulate dendritic cell differentiation and responses to TLR ligands. J. Leukoc. Biol. 88, 435–444 (2010).

  117. 117.

    et al. Uterine epithelial cell regulation of DC-SIGN expression inhibits transmitted/founder HIV-1 trans infection by immature dendritic cells. PLoS ONE 5, e14306 (2010). This study shows that uterine epithelial secretions containing TGFβ regulate the phenotypic characteristics and the function of DCs, as well as alter the DC-mediated infection of HIV-susceptible target cells.

  118. 118.

    et al. Characterization of CCL20 secretion by human epithelial vaginal cells: involvement in langerhans cell precursor attraction. J. Leuk. Biol. 78, 158–166 (2005).

  119. 119.

    et al. CCL20/MIP3α is a novel anti-HIV-1 molecule of the human female reproductive tract. Am. J. Reprod. Immunol. 62, 60–71 (2009).

  120. 120.

    et al. Trappin-2/elafin modulate innate immune responses of human endometrial epithelial cells to polyI:C. PLoS ONE 7, e35866 (2012).

  121. 121.

    et al. Toll-like receptor 4-dependent activation of dendritic cells by β-defensin 2. Science 298, 1025–1029 (2002).

  122. 122.

    et al. High susceptibility to repeated, low-dose, vaginal SHIV exposure late in the luteal phase of the menstrual cycle of pigtail macaques. J. Acquir. Immune Def. Syndr. 57, 261–264 (2011). This is the first study to provide evidence for the 'window-of-vulnerabilty' hypothesis by showing the effect of the menstrual cycle on SHIV infection in a non-human primate model.

  123. 123.

    et al. SHIV susceptibility changes during the menstrual cycle of pigtail macaques. J. Med. Primatol. 43, 310–316 (2014).

  124. 124.

    et al. Productive HIV-1 infection of human cervical tissue ex vivo is associated with the secretory phase of the menstrual cycle. Mucosal Immunol. 6, 1081–1090 (2013). Using ex vivo HIV infection of human cervico-vaginal tissues, this paper is the first demonstration that HIV infection in women occurs during the secretory but not the proliferative phase of the menstrual cycle.

  125. 125.

    et al. Estradiol reduces susceptibility of CD4+ T cells and macrophages to HIV-infection. PLoS ONE 8, e62069 (2013).

  126. 126.

    , & 17β-estradiol inhibits HIV-1 by inducing a complex formation between β-catenin and estrogen receptor α on the HIV promoter to suppress HIV transcription. Virology 443, 375–383 (2013).

  127. 127.

    et al. 17β-estradiol protects primary macrophages against HIV infection through induction of interferon-α. Viral. Immunol. 27, 140–150 (2014).

  128. 128.

    Influence of ovarian hormones on urogenital infection. Sex. Transm. Infect. 74, 11–19 (1998).

  129. 129.

    , , & Effect of estrogen (17 β-estradiol) on the susceptibility of mice to disseminated gonococcal infection. Infect. Immun. 49, 238–243 (1985).

  130. 130.

    , & Neisseria gonorrhoeae colonises the genital tract of oestradiol-treated germ-free female mice. Microb. Pathog. 9, 369–373 (1990).

  131. 131.

    , & Effects of reproductive hormones on experimental vaginal candidiasis. Infect. Immun. 68, 651–657 (2000).

  132. 132.

    , , & Estrogen enhances attachment of Chlamydia trachomatis to human endometrial epithelial cells in vitro. Am. J. Obstet. Gynecol. 159, 1006–1014 (1988).

  133. 133.

    , , & Estradiol limits viral replication following intravaginal immunization leading to diminished mucosal IgG response and non-sterile protection against genital herpes challenge. Am. J. Reprod. Immunol. 63, 299–309 (2010).

  134. 134.

    The ecology and evolutionary endocrinology of reproduction in the human female. Am. J. Physical Anthropol. 140, 95–136 (2009).

  135. 135.

    , , , & Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT analyzer. Clin. Chem. Lab. Med. 44, 883–887 (2006).

  136. 136.

    et al. Temporal relationships of estrogen, progesterone, and luteinizing hormone levels to ovulation in women and infrahuman primates. Am. J. Obstet. Gynecol. 130, 876–886 (1978).

  137. 137.

    et al. Immunohistochemical analysis of human uterine estrogen and progesterone receptors throughout the menstrual cycle. J. Clin. Endocrinol. Metab. 67, 334–340 (1988).

  138. 138.

    et al. Immunocytochemical analysis of oestrogen receptors and progesterone receptors in the human uterus throughout the menstrual cycle and after the menopause. J. Reprod. Fertil. 94, 363–371 (1992).

  139. 139.

    & Concentration of oestrone and oestradiol in follicular fluid and ovarian venous blood of women. Clin. Endocrinol. (Oxf.) 4, 259–266 (1975).

  140. 140.

    et al. Concentration of oestrogens and androgens in human ovarian venous plasma and follicular fluid throughout the menstrual cycle. J. Endocrinol. 71, 77–85 (1976).

  141. 141.

    et al. Concentration of unconjugated estrogens, androgens and gestagens in ovarian and peripheral venous plasma of women: the normal menstrual cycle. J. Clin. Endocrinol. Metab. 32, 155–166 (1971).

  142. 142.

    & The role of sexually transmitted diseases in HIV transmission. Nature Rev. Microbiol. 2, 33–42 (2004).

  143. 143.

    et al. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 20, 73–83 (2006).

  144. 144.

    et al. Increased susceptibility to vaginal simian/human immunodeficiency virus transmission in pig-tailed macaques coinfected with Chlamydia trachomatis and Trichomonas vaginalis. J. Infect. Dis. 210, 1239–1247 (2014).

  145. 145.

    et al. Potential mechanisms for increased HIV-1 transmission across the endocervical epithelium during C. trachomatis infection. Curr. HIV Res. 10, 218–227 (2012).

  146. 146.

    & Modulation of HIV transmission by Neisseria gonorrhoeae: molecular and immunological aspects. Curr. HIV Res. 10, 211–217 (2012).

  147. 147.

    et al. Influence of sex hormones, HIV status, and concomitant sexually transmitted infection on cervicovaginal inflammation. J. Infect. Dis. 191, 358–366 (2005).

  148. 148.

    et al. Physiology of upward transport in the human female genital tract. Ann. NY Acad. Sci. 1101, 1–20 (2007).

Download references

Acknowledgements

The authors express their appreciation to J. Fahey for help in editing this manuscript. This work was supported by US National Institutes of Health (NIH) grants AI102838, AI071761 and AI117739.

Author information

Affiliations

  1. Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA.

    • Charles R. Wira
    • , Marta Rodriguez-Garcia
    •  & Mickey V. Patel

Authors

  1. Search for Charles R. Wira in:

  2. Search for Marta Rodriguez-Garcia in:

  3. Search for Mickey V. Patel in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Charles R. Wira.

Glossary

Implantation

The binding to and invasion of the uterine endometrium by the blastocyst, which occurs 5–12 days after fertilization.

Proliferative phase

Days 5–14 of the classical menstrual cycle. Defined as the period between the end of menstrual bleeding and ovulation. Characterized by rising serum levels of oestradiol and very low levels of progesterone.

Secretory phase

Days 14–28 of the classical menstrual cycle. Defined as the period between ovulation and the initiation of menstrual bleeding. Characterized by high levels of both oestradiol and progesterone.

Corpus luteum

The tissue formed after ovulation by thecal and granulosa cells from the remains of the collapsed ovarian follicle; it is responsible for progesterone and oestradiol secretion during the secretory phase of the menstrual cycle. In the absence of fertilization, the corpus luteum degrades, thus decreasing hormone synthesis and signalling the initiation of menstruation.

Pattern-recognition receptors

(PRRs). Multiple families of conserved receptors, such as Toll-like receptors (TLRs), that are present on the cell surface or within intracellular compartments. PRRs recognize conserved structures that are present on pathogens or that are produced as part of their life cycle.

Pathogen-associated molecular patterns

(PAMPs). Conserved structures that are an integral part of pathogens but not mammalian cells and that are recognized by pattern- recognition receptors. Examples include viral and bacterial components such as double- and single-stranded RNA, bacterial lipopolysaccharide and hypomethylated DNA.

Cervico-vaginal lavage fluid

(CVL fluid). The fluid recovered after gently washing the vaginal walls and external cervix; it contains the cellular secretions present in the lower female reproductive tract.

Tight junction proteins

A group of proteins, including claudins and occludin, that form complexes to link adjacent epithelial cells, creating a polarized epithelium that provides a barrier and regulates the movement of molecules.

Decidualization

The changes to the endometrium that occur as it transitions to a pregnant state under the influence of progesterone. Characterized by vascular, stromal and epithelial changes that create a permissive uterine environment for implantation.

TZM-bl cells

Modified HeLa cells that express high levels of the HIV receptor CD4, the co-receptors CC-chemokine receptor 5 (CCR5) and CXC-chemokine receptor 4 (CXCR4), and a Tat-induced β-galactosidase cassette.

Lamina basalis

The lower layer of the uterine endometrium that is not shed at menses and from which the functionalis layer is reconstituted during the proliferative phase of the menstrual cycle.

Functionalis layer

The upper layer of the uterine endometrium that is shed at menses.

Innate lymphoid cell

(ILC). An innate immune cell with classical lymphoid morphology that lacks cell lineage markers and antigen specificity. ILCs are heterogeneous and include cytotoxic natural killer cells and cytokine-producing non-cytotoxic helper ILC populations.

Alternatively activated macrophages

Macrophages that have been activated by the T helper 2 cell-type cytokines interleukin-4 (IL-4) and IL-13, as opposed to the classical interferon-γ (IFNγ) activation pathway. Alternative activation confers a phenotype that is instrumental in immune regulation and tissue repair.

Viral eclipse phase

The interval of time after viral infection during which the virus cannot be detected.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nri3819

Further reading

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing