Changes in concentrations of cervicovaginal immune mediators across the menstrual cycle: a systematic review and meta-analysis of individual patient data
Authors: Hughes Sean M. , Levy Claire N. , Katz Ronit , Lokken Erica M. , Anahtar Melis N. , Hall Melissa Barousse , Bradley Frideborg , Castle Philip E. , Cortez Valerie , Doncel Gustavo F. , Fichorova Raina , Fidel Paul L. , Fowke Keith R. , Francis Suzanna C. , Ghosh Mimi , Hwang Loris Y. , Jais Mariel , Jespers Vicky , Joag Vineet , Kaul Rupert , Kyongo Jordan , Lahey Timothy , Li Huiying , Makinde Julia , McKinnon Lyle R. , Moscicki Anna-Barbara , Novak Richard M. , Patel Mickey V. , Sriprasert Intira , Thurman Andrea R. , Yegorov Sergey , Mugo Nelly Rwamba , Roxby Alison C. , Micks Elizabeth , Hladik Florian ,   The Consortium for Assessing Immunity Across the Menstrual Cycle, Abdool Karim Salim S. , Abou Max , Anderson Sharon M. , Andreasen Aura , Ao Trong T. , Archer David F. , Arien Kevin K. , Arnold Kelly B. , Asin Susana , Baden Susan , Bagaya Bernard S. , Baisley Kathy , Barnard Emma , Bartolf Angela , Bernick Brian A. , Birse Kenzie , Boggild Andrea K. , Boily-Larouche Genevieve , Boksa Lucy A. , Bowman Brittany A. , Bowman Fredrick P. , Broliden Kristina , Burgener Adam D. , Buyze Jozefien , Byrne Elizabeth H. , Chandra Neelima , Chapman Stacey , Chen Hua Yun , Cheruiyot Juliana , Chesson Ralph R. , Cohen Kathleen E. , Cools Piet , Cosgrove Catherine , Coulton Gary R. , Crowley-Nowick Peggy A. , Crucitti Tania , Cunningham Tina D. , Cu-Uvin Susan , Dawood Hassan Y. , Delany-Moretlwe Sinead , Dong Krista L. , Donoval Betty A. , Dufault Brenden , Dunlap Kathleen , Dunphy Laura J. , Edwards Robert P. , Engstrand Lars , Espinosa Terri , Fahey John V. , Fashemi Titilayo , Fortenberry J. Dennis , Freiermuth Jamie L. , Galiwango Ronald M. , Ghebremichael Musie S. , Good Sara V. , Goovaerts Odin , Graham Parrie J. , Hardy Liselotte , Hasselrot Klara , Hayes Richard J. , Herold Betsy C. , Herrera Carolina , Hershow Ronald C. , Hildesheim Allan , Hillier Sharon , Hou Yanwen , Huang Hazel , Hughes Sean M. , Hwang Loris Y. , Introini Andrea , Ismail Nasreen , Jacot Terry , Jais Mariel , Jespers Vicky , Joag Vineet , Johnston Christine , Jones Clifford , Joseph Sarah , Kapiga Saidi , Kappes John C. , Kimani Joshua , Kimani Makobu , Kimble Thomas , Kiwanuka Noah , Kowatsch Monika , Kwatampora Jessie , Kwon Douglas S. , Lajoie Julie , Landay Alan , Lauffenburger Douglas A. , Lehman Dara A. , Leslie Alasdair , Liebenberg Lenine J. , Lieberman Jay A. , Lounev Vitali , Ma Yifei , Mabhula Amanda , Mabuka Jennifer , Maganja Kaballa , Marrazzo Jeanne , Masson Lindi , Mayer Kenneth H. , McCorrister Stuart , Menten Joris , Mesquita Pedro M. M. , Michiels Johan , Mirkin Sebastian , Moodley Amber , Mpendo Juliet , Mukura Lucy R. , Mwaura Mary , Ndayisaba Gilles , Ndung’u Thumbi , Njoki Jane , Noel-Romas Laura , Nyanga Billy , Ochsenbauer Christina , Odem-Davis Katherine , Olson Gregory S. , Omollo Kenneth , Orr Donald P. , Overbaugh Julie , Oyugi Julius , Padavattan Nikita , Pakrashi Tarita , Pandey Urvashi , Passmore Jo-Ann S. , Pustilnik Terri , Rabe Lorna , Richardson-Harman Nicola , Rollenhagen Christiane , Romas Laura , Rossoll Richard M. , Schwartz Jill L. , Scott Mark E. , Seifert Maike , Shah A. , Shahabi Kamnoosh , Shattock Robin J. , Shen Zheng , Shi Baochen , Sibeko Sengeziwe , Song Yan , Spear Gregory , Starkman Brian S. , Strickler Howard D. , Sumerel Jan L. , Tannich Egbert , Theall Katherine P. , Tjernlund Annelie , van de Wijgert Janneke , Van Der Pol Barbara , Vanham Guido , Walker Bruce D. , Walker Joan L. , Watson-Jones Deborah , Wefer Hugo , Westmacott Garrett R. , Wira Charles R. , Wright Peter F. , Younes Naji , Yousefieh Nazita 
Published: October 2022

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.