The Role of Immune and Oxidative Pathways in Menstrual-Cycle Associated Depressive, Physio-Somatic, Breast and Anxiety Symptoms: Modulation by Sex Hormones

Abstract

Objective: To examine whether 1) immune and nitro-oxidative stress (IO&NS) biomarkers are associated with premenstrual syndrome (PMS); and 2) changes in IO&NS biomarkers during the menstrual cycle (MC) are associated with PMS symptoms and plasma estradiol and progesterone. Methods: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days and MC Associated Syndrome (MCAS) was diagnosed when the summed DRSP score during the MC is > 0.666 percentile. We assayed plasma levels of complement C3 and C4, highly sensitive C-reactive protein (hsCRP), haptoglobin (Hp), advanced oxidation protein products (AOPP), lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP), sulfhydryl (-SH) groups and the activity of paraoxonase (PON)1 at days 7 (D7), 14 (D14), 21 (D21) and 28 (D28) of the MC. Results: All biomarkers, except hsCRP, showed significant alterations during the MC. Arylesterase (AREase) was lowered at D28, while LOOH increased at D14 and C4 at D21 in women with MCAS. The total DRSP score was predicted by the combined effects of C4 (positively) and AREase and malondialdehyde (MDA) (both inversely associated). Progesterone lowered levels of LOOH, AOPP and C3 and estradiol lowered levels of Hp while both sex hormones increased 4-(chloromethyl)phenyl acetate (CMPA)ase and AREase activities and levels of -SH groups. Conclusion: PMS/MCAS is not accompanied by a peripheral inflammatory response. Lowered MDA and antioxidant defenses and increased C4 may play a role in MC-associated symptoms while sex hormones may have a protective effect against oxidative stress toxicity.

Menstruation Distress Is Strongly Associated with Hormone-Immune-Metabolic Biomarkers

“…Hp is significantly higher at the end of the menstruation as compared with the luteal phase [14] and is increased in uterine fluid during the secretory phase [22]. Hp is an acute phase reactant and is elevated in endometritis and inflammation of the uterine endometrium [68].…”

“…The intra-assay coefficients of variation were <10% for all analytes. In the present study, we also used the sum of the biomarkers obtained at the 4 time points during the menstrual cycle [14]…”

“…Recently we showed that PMS, as defined using a new case definition, namely menstrualcycle-associated syndrome (MCAS), is caused by a relative corpus luteum insufficiency (insufficient progesterone production), which, in part may result from suboptimal pre-ovulatory follicular development (lowered estradiol production) while also immune-oxidative pathways are involved [12][13][14]. The latter include increased levels of a) uterus-associated chemokines such as chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 11 or eotaxin (CCL11), and regulated on activation, normal T cell expressed and secreted (CCL5); growth factors including epidermal growth factor (EGF), and lowered levels of paraoxonase (PON)1, an antioxidant enzyme that can hydrolyze lipid peroxides thereby protecting low and high-density lipoprotein (LDL-HDL) against oxidation [15] [16, 17].…”

“…Wander et al (2008) found that menstruation is associated with a 17% increase in C-reactive protein (CRP), whereby a 10-fold increase in progesterone is associated with a 23% increase in CRP and a 10-fold increase in estrogen with a 29% decrease in CRP [21]. Haptoglobin (Hp), an acute phase response, is increased immediately after menses as compared with the luteal phase and is increased in uterine fluid during the secretory phase [14,22]. Regulated upon activation, normal T cell expressed and secreted (RANTES or CCL5) is a chemokine attracting monocytes and activated T cells that is synthesized by stromal cells of both normal endometrium and endometriosis tissues [23].…”