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

Richard M Novak, Vineet Joag, Rupert Kaul, Jordan Kyongo, Timothy Lahey, Huiying Li, Julia Makinde, Lyle R McKinnon, Anna-Barbara Moscicki, Vicky Jespers, Mickey V Patel, Intira Sriprasert, Andrea R Thurman, Sergey Yegorov, Nelly Rwamba Mugo, Alison C Roxby, Elizabeth Micks, Florian Hladik, Gustavo F Doncel, Sean M Hughes, Claire N Levy, Erica M Lokken, Melis N Anahtar, Melissa Barousse Hall, Frideborg Bradley, Philip E Castle, Valerie Cortez, Ronit Katz, Raina Fichorova, Paul L Fidel, Keith R Fowke, Suzanna C Francis, Mimi Ghosh, Loris Y Hwang, Mariel Jais

Journal: BMC medicine 2022;20(1):353

PMID: 36195867

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.

© 2022. The Author(s).

Address: Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA.; Department of Global Health, University of Washington, Seattle, WA, USA.; Ragon Institute of MIT and Harvard, Massachusetts General Hospital, Boston, MA, USA.; University of Louisville, Louisville, KY, USA.; Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.; Department of Molecular, Cell & Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA, USA.; CONRAD, Eastern Virginia Medical School, Norfolk, VA, USA.; Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.; Louisiana State University Health, New Orleans, LA, USA.; Department of Medical Microbiology & Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada.; MRC International Statistics and Epidemiology Group, London School of Hygiene and Tropical Medicine, London, UK.; Department of Epidemiology, The George Washington University, Washington, DC, USA.; Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, USA.; Office of Laboratory Safety, The George Washington University, Washington, DC, USA.; Institute of Tropical Medicine, Antwerp, Belgium.; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA.; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.; Virology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.; University of Vermont Larner College of Medicine, Burlington, VT, USA.; Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA.; IAVI Human Immunology Laboratory, Imperial College, London, England, UK.; IAVI, New York, NY, USA.; Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.; Department of Medical Microbiology and Immunology, University of Nairobi, Nairobi, Kenya.; University of Illinois, Chicago, IL, USA.; Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.; Department of OB/GYN, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.; Center for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.; Department of Medicine, University of Washington, Seattle, WA, USA.; Vaccine and Infectious Disease Division, Fred Hutch, Seattle, WA, USA.; Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA. [email protected].; Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA. [email protected].; Department of Medicine, University of Washington, Seattle, WA, USA. [email protected].; Vaccine and Infectious Disease Division, Fred Hutch, Seattle, WA, USA. [email protected].
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