The Uterine-Chemokine-Brain Axis: Menstrual Cycle-Associated Symptoms (MCAS) Are in Part Mediated by CCL2, CCL5, CCL11, CXCL8 and CXCL10

Abstract

Objective: To examine associations between chemokines and menstrual cycle associated symptoms (MCAS). Methods: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days of the menstrual cycle. is diagnosed when the total daily DRSP score during the menstrual cycle is > 0.666 percentile. We assayed plasma CCL2, CCL5, CCL11, CXCL8, CXCL10, EGF, IGF-1, and PAI-1 at days 7, 14, 21 and 28 of the menstrual cycle. Results: CCL2, CCL5, CCL11 and EGF are significantly higher in women with than in those without. Increased CCL2, CXCL10, CXCL8, CCL11 and CCL5 levels are significantly associated with DRSP scores while CCL2 is the most significant predictor explaining 39.6% of the variance. The sum of the neurotoxic chemokines CCL2, CCL11 and CCL5 is significantly associated with the DRSP score and depression, physiosomatic, breast-craving and anxiety symptoms. The impact of chemokines on symptoms may differ between consecutive weeks of the menstrual cycle with CCL2 being the most important predictor of increased DRSP levels during the first two weeks, and CXCL10 or a combination of CCL2, CCL11 and CCL5 being the best predictors during week 3 and 4, respectively. Discussion: The novel case definition MCAS is externally validated by increased levels of uterus-associated chemokines and EGF. Those chemokines are involved in and are regulated by sex hormones and modulate endometrium functions and brain neuro-immune responses, which may underpin symptoms. As such, uterine-related chemokines may link the uterus with brain functions via a putative uterine-chemokine-brain axis. Funding Statement: This research has been supported by 1) the Ratchadaphiseksomphot Fund, Faculty of Medicine, Chulalongkorn University, grant number RA61/016; 2) Chulalongkorn University; Government Budget; and 3) the Ratchadaphiseksomphot Fund, Chulalongkorn University. Declaration of Interests: The authors have no conflict of interest with any commercial or other association in connection with the submitted article. Ethics Approval Statement: The study was approved by the Ethics Committee of the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand (IRB No.611/60, COA No. 1111/2017). Written informed consent was obtained from all participants prior to the study.