Table 3.
Molecular determinants, their function in normal pregnancy, and changes in RPL and RIF.
| Hormone/Cytokine/Glycoprotein | Normal Pregnancy | RPL | RIF |
|---|---|---|---|
| Estrogen | Proliferation of endometrium, ERα: essential for implantation, ERβ: no restriction of fertility | Estrogen ↓ [17,19] | Estrogen ↓ [23,24] Estrogen ↑ → premature progesterone influence [23] |
| Progesterone | Inducing decidualization, opening the WOI PR-A (PR-B knock-out): implantation, pregnancy, parturation PR-B (PR-A knock-out): endometrial hyperplasia, inflammation, absence of decidualization |
Progesterone ↓ [19] | Estrogen ↑ → premature progesterone influence, asynchronicity between endometrium and embryo [23] |
| IL-6 | Luteal phase: high concentration, regulation of trophoblast invasion and spiral artery remodeling | Sporadic abortion: IL-6 ↓ [37] RPL: IL-6 ↑ [39] |
IL-6 ↑ [41] IL-6 = [43] IL-6 = [42] |
| IL-8 | Luteal phase and during embryo presentation: high concentration; stimulates progesterone secretion | Sporadic abortion: IL-8 ↓ [37] RPL: IL-8 ↑ [39] |
IL-8 ↑ [42] |
| LIF | Receptivity of endometrium, decidualization, maintaining pinopodes, embryo attachment, implantation, placenta development | LIF ↑ (endometrial samples) [52] LIF = (endometrial samples) [53] LIF ↓ (serum) [54] |
LIF ↓ (secretory phase), high amplitude (proliferative phase) [55] LIF ↓ (proliferative phase) [56] KLF12 ↑ → LIF ↓ [57] |
| IL-11 | Produced by stromal and epithelial cells, during early secretory phase (epithelial cells), during decidualization (stromal cells), TNF-α ↓ | IL-11 (epithelial cells) ↓ [64] | IL-11 (stromal cells) ↓ [65] IL-11 = [66] |
| IL-1 | IL-1β and IL-1Ra are responsible for the embryo–maternal dialog and the immunological shift. The tissue of the fallopian tubes and the myometrial smooth muscle synthesize IL-1β during pregnancy, IL-1β ↑ during pregnancy, responsible for prothrombotic state | IL-1β ↓ [67,75] IL-1β ↑ [76] IL-1β ↑ and antiphospholipid syndrome [78] |
IL-1β= no increase in contrast to healthy pregnancies, IL1-Ra = [79], IL-1 β ↑ [41,80,81] |
| Glycodelin | Glycodelin-A: shifting the immune system, endometrial proliferation, fertilization and implantation | Glycodelin-A ↓ [85,86] | Glycodelin-A ↓ [87,88] |
Abbreviations: ER: estrogen receptor, PR: progesterone receptor, WOI: window of implantation, IL-1Ra: IL-1 receptor antagonist, KLF12: Krüppel-like factor 12, ↑: higher expression compared to regular implantation, =: no changes concerning the expression, ↓: lower expression compared to regular implantation, →: leading to.