The Impact of the Ovulatory Cycle on Cytokine Production: Evaluation of Systemic, Cervicovaginal, and Salivary Compartments

Abstract

To understand the impact of the menstrual cycle on immunologic parameters, we measured the level of cytokines and chemokines from plasma, cervicovaginal lavage (CVL), and saliva samples of 6 premenopausal women during the follicular and luteal phases of the ovulatory cycle. We demonstrate that the level of plasma interleukin-8 (IL-8) was 4-fold higher during the follicular phase than the luteal phase (p = 0.004), whereas plasma IL-1beta, IL-4, IL-6, IL-10, interferon-gamma (IFN-gamma), transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha), and TNF receptor II (TNFR II) were not altered during the ovulatory cycle. In the vaginal compartment, as measured from CVL samples, the levels of IL-6 and IL-1beta were both 5-fold higher in the follicular than the luteal phase (p = 0.0002 and 0.03, respectively). Salivary cytokine and chemokine samples were similar when measured during the luteal and the follicular phases. Additional analysis of lymphocyte subsets for phenotypic and functional markers indicated that they were not influenced by the ovulatory cycle. Collectively, these data suggest that IL-6, IL-8, and IL-1beta are differentially regulated during the ovulatory cycle.

Comparison of Follicular and Luteal Phase Mucosal Markers of HIV Susceptibility in Healthy Women

“…20 Secretion of mannosebinding lectin, a molecule in the complement system that plays a critical role in host protection, from vaginal epithelial cells is increased in the LUT phase of the menstrual cycle. 49 Other investigations found that CV immune mediators did not change based on the menstrual cycle (e.g., IL-10, TNF-a, IL-8, RANTES, and TNFR II), 19,26,50 but were higher during menstruation. 26,50 Genital tract cytokines have also been shown to vary based on clinical factors, such as cervical ectopy, inflammation, and sexual activity.…”

“…45 No significant differences in the antimicrobial activity of the CVL The secretion of cervical mucus is significantly influenced by endogenous reproductive hormones, with cervical mucus volume peaking with surges in preovulatory serum E2. [46][47][48] The biologic rationale for differences in antimicrobial activity of the CVL is based on data from small cohorts showing that secreted cytokines, chemokines, and other cationic antimicrobial polypeptides in the vagina have significant alterations in concentrations based on the phase of the menstrual cycle with immune factors such as IL-6, IL-1b, IL-1RA, and MIP-1b being significantly higher in the FOL phase versus the LUT phase, 19,27 while IL-1a and b-defensin were significantly elevated in the LUT phase. 27 Keller et al found that immune mediators, SLPI, a and b defensins, lysozyme, and lactoferrin, were significantly lower at mid-cycle ovulation compared with both the FOL and LUT phases.…”

“…14 Much of the data supporting mucosal vulnerability to HIV infection in the LUT phase come from evidence of immune suppression, increases in HIV target cells, 15 or other interactions between the immune and endocrine systems found in studies of endometrial explants [15][16][17] (reviewed in Wira and Fahey 11 ) or data showing increases in proinflammatory cytokines in endocervical mucus. 18 However, there is a paucity of data regarding the effect of the menstrual cycle on immune cell recruitment and activation in the lower reproductive tract, including the ectocervix and vagina, 19,20 with some studies showing no changes in CD4 and CCR5-positive cells, based on the menstrual cycle, in ectocervical explants. 21 Previous studies regarding the effect of endogenous hormones on mucosal HIV targets in the lower genital tract have been done primarily with explants obtained from women undergoing elective surgeries such as hysterectomies [21][22][23][24][25] or among small cohorts of women in a longitudinal 19,[26][27][28] or cross-sectional design.…”

“…18 However, there is a paucity of data regarding the effect of the menstrual cycle on immune cell recruitment and activation in the lower reproductive tract, including the ectocervix and vagina, 19,20 with some studies showing no changes in CD4 and CCR5-positive cells, based on the menstrual cycle, in ectocervical explants. 21 Previous studies regarding the effect of endogenous hormones on mucosal HIV targets in the lower genital tract have been done primarily with explants obtained from women undergoing elective surgeries such as hysterectomies [21][22][23][24][25] or among small cohorts of women in a longitudinal 19,[26][27][28] or cross-sectional design. 29 While surgical explants offer convenience and supply tissue without invasive biopsy procedures, women undergoing indicated surgery invariably have a host of medical comorbidities and concomitant medication use, which may affect study endpoints.…”

T helper 1-type immunity to trophoblast antigens in women with a history of recurrent pregnancy loss is associated with polymorphism of the IL1B promoter region

“…In addition, Th1 cytokine production by PBMCs in response to trophoblast extracts was not influenced by when in the menstrual cycle the study samples were obtained (Hill JA, unpublished results), which is consistent with relevant data from other published reports, 31 although the levels of IL-4 produced by PBMCs and IL-1 and IL-8 in serum may vary between the two phases of the menstrual cycle. [31][32][33] Therefore, Th1 immunity to trophoblast, which is associated with IL1B polymorphism in women with RPL, appears to be a specific memory immune response. To our knowledge, ours is the first study demonstrating that polymorphisms of a cytokine gene, IL1B are associated with Th1 immunity to trophoblast in women with RPL.…”