Changes in concentrations of cervicovaginal immune mediators across the menstrual cycle: a systematic review and meta-analysis of individual patient data
Sean M. Hughes,
Claire N. Levy,
Ronit Katz,
Erica M. Lokken,
Melis N. Anahtar,
Melissa Barousse Hall,
Frideborg Bradley,
Philip E. Castle,
Valerie Cortez,
Gustavo F. Doncel,
Raina Fichorova,
Paul L. Fidel,
Keith R. Fowke,
Suzanna C. Francis,
Mimi Ghosh,
Loris Y. Hwang,
Mariel Jais,
Vicky Jespers,
Vineet Joag,
Rupert Kaul,
Jordan Kyongo,
Timothy Lahey,
Huiying Li,
Julia Makinde,
Lyle R. McKinnon,
Anna-Barbara Moscicki,
Richard M. Novak,
Mickey V. Patel,
Intira Sriprasert,
Andrea R. Thurman,
Sergey Yegorov,
Nelly Rwamba Mugo,
Alison C. Roxby,
Elizabeth Micks,
Florian Hladik,
The Consortium for Assessing Immunity Across the Menstrual Cycle
Affiliations
Sean M. Hughes
Department of Obstetrics and Gynecology, University of Washington
Claire N. Levy
Department of Obstetrics and Gynecology, University of Washington
Ronit Katz
Department of Obstetrics and Gynecology, University of Washington
Erica M. Lokken
Department of Obstetrics and Gynecology, University of Washington
Melis N. Anahtar
Ragon Institute of MIT and Harvard, Massachusetts General Hospital
Melissa Barousse Hall
University of Louisville
Frideborg Bradley
Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital
Philip E. Castle
Division of Cancer Prevention, National Cancer Institute, National Institutes of Health
Valerie Cortez
Department of Molecular, Cell & Developmental Biology, University of California, Santa Cruz
Gustavo F. Doncel
CONRAD, Eastern Virginia Medical School
Raina Fichorova
Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Brigham and Women’s Hospital
Paul L. Fidel
Louisiana State University Health
Keith R. Fowke
Department of Medical Microbiology & Infectious Diseases, University of Manitoba
Suzanna C. Francis
MRC International Statistics and Epidemiology Group, London School of Hygiene and Tropical Medicine
Mimi Ghosh
Department of Epidemiology, The George Washington University
Loris Y. Hwang
Department of Pediatrics, University of California, Los Angeles
Mariel Jais
Office of Laboratory Safety, The George Washington University
Vicky Jespers
Institute of Tropical Medicine
Vineet Joag
Department of Microbiology and Immunology, University of Minnesota
Rupert Kaul
Department of Medicine, University of Toronto
Jordan Kyongo
Virology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine
Timothy Lahey
University of Vermont Larner College of Medicine
Huiying Li
Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, University of California, Los Angeles
Julia Makinde
IAVI Human Immunology Laboratory, Imperial College
Lyle R. McKinnon
Department of Medical Microbiology & Infectious Diseases, University of Manitoba
Anna-Barbara Moscicki
Department of Pediatrics, University of California, Los Angeles
Richard M. Novak
University of Illinois
Mickey V. Patel
Geisel School of Medicine at Dartmouth
Intira Sriprasert
Department of OB/GYN, Keck School of Medicine, University of Southern California
Andrea R. Thurman
CONRAD, Eastern Virginia Medical School
Sergey Yegorov
Department of Biochemistry and Biomedical Sciences, McMaster University
Nelly Rwamba Mugo
Department of Global Health, University of Washington
Alison C. Roxby
Department of Global Health, University of Washington
Elizabeth Micks
Department of Obstetrics and Gynecology, University of Washington
Florian Hladik
Department of Obstetrics and Gynecology, University of Washington
The Consortium for Assessing Immunity Across the Menstrual Cycle
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.
