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.


METHODS
Prospective, observational study.


METHODS
Academic medical center.


METHODS
Six fertile volunteers studied over two menstrual cycles.


METHODS
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.


METHODS
Concentrations of leukemia inhibitory factor (LIF), macrophage-colony stimulating factor (M-CSF), interleukin-1beta (IL-1beta), transforming growth factor-beta1 (TGF-beta1), TGF-beta2, 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.


RESULTS
Macrophage-colony stimulating factor and EGF were detectable in all CVL samples. Macrophage-colony stimulating factor concentrations were positively correlated with serum E2 levels and the E2/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.


CONCLUSIONS
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.
Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. agargiulo@partners.org
Antonio R
AR
Gargiulo
Raina N
RN
Fichorova
Joseph A
JA
Politch
Joseph A
JA
Hill
Deborah J
DJ
Anderson
D000328:Adult; D002584:Cervix Uteri / Q000378:metabolism*; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D010064:Embryo Implantation / Q000502:physiology*; D004717:Endometrium / Q000378:metabolism; D005260:Female; D005298:Fertility; D006728:Hormones / Q000097:blood; D006801:Humans; D008597:Menstrual Cycle / Q000502:physiology*; D009994:Osmolar Concentration; D010060:Ovulation / Q000378:metabolism*; D011446:Prospective Studies; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values; D015203:Reproducibility of Results; D007507:Therapeutic Irrigation; D014599:Uterus / Q000378:metabolism*
D016207:Cytokines; D006728:Hormones; D012333:RNA, Messenger