Changes in concentrations of cervicovaginal immune mediators across the menstrual cycle: a systematic review and meta-analysis of individual patient data

Sean M. Hughes, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA.
Claire N. Levy, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA.
Ronit Katz, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA.
Erica M. Lokken, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA.
Melis N. Anahtar, Ragon Institute of MIT and Harvard, Massachusetts General Hospital, Boston, MA, USA.
Melissa Barousse Hall, University of Louisville, Louisville, KY, USA.
Frideborg Bradley, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Philip E. Castle, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.
Valerie Cortez, Department of Molecular, Cell & Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA, USA.
Gustavo F. Doncel, CONRAD, Eastern Virginia Medical School, Norfolk, VA, USA.
Raina Fichorova, Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
Paul L. Fidel, Louisiana State University Health, New Orleans, LA, USA.
Keith R. Fowke, Department of Medical Microbiology & Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada.
Suzanna C. Francis, MRC International Statistics and Epidemiology Group, London School of Hygiene and Tropical Medicine, London, UK.
Mimi Ghosh, Department of Epidemiology, The George Washington University, Washington, DC, USA.
Loris Y. Hwang, Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, USA.
Mariel Jais, Office of Laboratory Safety, The George Washington University, Washington, DC, USA.
Vicky Jespers, Institute of Tropical Medicine, Antwerp, Belgium.
Vineet Joag, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA.
Rupert Kaul, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Jordan Kyongo, Virology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
Timothy Lahey, University of Vermont Larner College of Medicine, Burlington, VT, USA.
Huiying Li, Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA.
Julia Makinde, IAVI Human Immunology Laboratory, Imperial College, London, England, UK.
Lyle R. McKinnon, Department of Medical Microbiology & Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada.
Anna-Barbara Moscicki, Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, USA.
Richard M. Novak, University of Illinois, Chicago, IL, USA.
Mickey V. Patel, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
Intira Sriprasert, Department of OB/GYN, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Andrea R. Thurman, CONRAD, Eastern Virginia Medical School, Norfolk, VA, USA.
Sergey Yegorov, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Nelly Rwamba Mugo, Department of Global Health, University of Washington, Seattle, WA, USA.

Document Type

Journal Article

Publication Date

10-5-2022

Journal

BMC medicine

Volume

20

Issue

1

DOI

10.1186/s12916-022-02532-9

Keywords

Cervix; Chemokine; Cytokine; Female genital tract; Menstrual cycle; Meta-analysis; Systematic review; vagina

Abstract

BACKGROUND: Hormonal changes during the menstrual cycle play a key role in shaping immunity in the cervicovaginal tract. Cervicovaginal fluid contains cytokines, chemokines, immunoglobulins, and other immune mediators. Many studies have shown that the concentrations of these immune mediators change throughout the menstrual cycle, but the studies have often shown inconsistent results. Our understanding of immunological correlates of the menstrual cycle remains limited and could be improved by meta-analysis of the available evidence. METHODS: We performed a systematic review and meta-analysis of cervicovaginal immune mediator concentrations throughout the menstrual cycle using individual participant data. Study eligibility included strict definitions of the cycle phase (by progesterone or days since the last menstrual period) and no use of hormonal contraception or intrauterine devices. We performed random-effects meta-analyses using inverse-variance pooling to estimate concentration differences between the follicular and luteal phases. In addition, we performed a new laboratory study, measuring select immune mediators in cervicovaginal lavage samples. RESULTS: We screened 1570 abstracts and identified 71 eligible studies. We analyzed data from 31 studies, encompassing 39,589 concentration measurements of 77 immune mediators made on 2112 samples from 871 participants. Meta-analyses were performed on 53 immune mediators. Antibodies, CC-type chemokines, MMPs, IL-6, IL-16, IL-1RA, G-CSF, GNLY, and ICAM1 were lower in the luteal phase than the follicular phase. Only IL-1α, HBD-2, and HBD-3 were elevated in the luteal phase. There was minimal change between the phases for CXCL8, 9, and 10, interferons, TNF, SLPI, elafin, lysozyme, lactoferrin, and interleukins 1β, 2, 10, 12, 13, and 17A. The GRADE strength of evidence was moderate to high for all immune mediators listed here. CONCLUSIONS: Despite the variability of cervicovaginal immune mediator measurements, our meta-analyses show clear and consistent changes during the menstrual cycle. Many immune mediators were lower in the luteal phase, including chemokines, antibodies, matrix metalloproteinases, and several interleukins. Only interleukin-1α and beta-defensins were higher in the luteal phase. These cyclical differences may have consequences for immunity, susceptibility to infection, and fertility. Our study emphasizes the need to control for the effect of the menstrual cycle on immune mediators in future studies.

Department

Epidemiology

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