Detection of implantation-related cytokines in cervicovaginal secretions and peripheral blood of fertile women during ovulatory menstrual cycles

Objective: To determine whether cytokines implicated in uterine receptivity are detectable in cervicovaginal secretions and/or serum of fertile women, and whether their concentrations undergo hormonal regulation during the menstrual cycle. Design: Prospective, observational study. Setting: Academic medical center. Patient(s): Six fertile volunteers studied over two menstrual cycles. Intervention(s): Cervicovaginal lavages (CVLs) and peripheral blood specimens were obtained during the menstrual, proliferative, periovulatory, and midsecretory phases of the cycle. Endometrial biopsies were obtained during the midsecretory phase. Main Outcome Measure(s): Concentrations of leukemia inhibitory factor (LIF), macrophage-colony stimulating factor (M-CSF), interleukin-1beta (IL-1beta), transforming growth factor-beta1 (TGF-beta1), TGF-beta1, and epidermal growth factor (EGF) in CVL and peripheral blood of fertile women; endometrial cytokine messenger (m)RNA levels in midsecretory phase; and serum E-2 and P levels throughout the menstrual cycle. Result(s): Macrophage-colony stimulating factor and EGF were detectable in all CVL samples. Macrophage-colony stimulating factor concentrations were positively correlated with serum E-2 levels and the E-2/P ratio. Whereas EGF concentrations in serum and CVL samples remained constant throughout the menstrual cycle, individual concentrations during the secretory phase of the menstrual cycle were positively correlated with endometrial EGF mRNA levels. Interleukin-1beta, TGF-beta1, and TGF-beta2 were detected in most CVL samples. Interleukin-1beta concentrations in CVL were significantly higher at menses than at the periovulatory stage of the menstrual cycle; TGF-beta2 levels were higher at menses than at the periovulatory and secretory stages. Leukemia inhibitory factor was undetectable in CVL except at menses. In serum, TGF-beta1, TGF-beta2, M-CSF, and EGF were detectable, but there was no menstrual cycle effect. There were no correlations between cytokine levels in CVL and serum. Conclusion(s): This study demonstrates that several endometrial cytokines that have been implicated in uterine receptivity are detectable in cervicovaginal secretions and peripheral blood of reproductive-aged women, and it provides normal concentration ranges of these cytokines in CVL and serum of fertile women at four stages of the menstrual cycle. Macrophage-colony stimulating factor and EGF warrant further study in CVLs of fertile and infertile women to determine their predictive value as minimally invasive markers of uterine receptivity. (C) 2004 by American Society for Reproductive Medicine.