**9. Master Regulators of Decidualization**

In order to promote optimal implantation/placentation and a healthy pregnancy, the endometrium must be optimally primed hormonally, biochemically, and immunologically during the luteal phase of the menstrual cycle (Figure 2).


and supporting embryo implantation. Glucose also serves as a metabolic signal for decidualization, providing a link between glycemic control and cellular oxidative stress (discussed below).

• Immunological factors. The importance of the immunological priming of the endometrium is becoming increasingly apparent. While this is driven, in part, by intrinsic factors, including a range of endocrine and autocrine/paracrine signals [3,17,35], extrinsic factors are likely also involved. One such factor is exposure to seminal fluid both prior to and around the time of implantation [74–76]. Interestingly, this exposure does not have to be local. Exposure to paternal antigen via nonvaginal routes can also prime the endometrium immunologically [77]. Although the mechanism responsible for this priming effect is not clear, seminal fluid contains soluble and exosome-borne signaling agents that promote leukocyte recruitment and generation of regulatory T cells (Treg cells) which suppress inflammation, promote vascular adaptation, and foster tolerance towards fetal antigens [78]. This mechanism could shed light on a number of well-recognized risk factors for the 'great obstetrical syndromes' that have thus far defied explanation. Why is it that nulliparity, young maternal age, IVF conception, the use of donor sperm, the short length of cohabitation, short inter-pregnancy interval, and the use of barrier contraception are risk factors for conditions such as preeclampsia and PTB? Could the common factor be a lack of exposure to protective seminal fluid? Recent data suggest that intercourse during IVF treatment cycles improves implantation success and pregnancy health [79], which is consistent with the hypothesis that exposure to seminal fluid promotes healthy decidualization and implantation. *Int. J. Mol. Sci.* **2020**, *21*, x FOR PEER REVIEW 6 of 20

**Figure 2.** Molecular pathways involved in decidualization. on a number of well-recognized risk factors for the 'great obstetrical syndromes' that have thus **Figure 2.** Molecular pathways involved in decidualization.

gonado-tropin; IGFBP1, isulin-like growth factor binding protein 1; IFN, interferon; IL-1β, interleukin-1β; ROS, reactive oxygen species; LIF, leukemia inhibitory factor; MET, mesenchymal-epithelial transition; miRNA, microRNA; MMP, matrix metalloproteinase; PGS, prostaglandins; TGF-β, transforming growth factor-β; TIMP, tissue inhibitor of meatalloproteinase;

• Immunological factors. The importance of the immunological priming of the endometrium is becoming increasingly apparent. While this is driven, in part, by intrinsic factors, including a range of endocrine and autocrine/paracrine signals [3,17,35], extrinsic factors are likely also involved. One such factor is exposure to seminal fluid both prior to and around the time of implantation [74–76]. Interestingly, this exposure does not have to be local. Exposure to paternal antigen via nonvaginal routes can also prime the endometrium immunologically [77]. Although the mechanism responsible for this priming effect is not clear, seminal fluid contains soluble and exosome-borne signaling agents that promote leukocyte recruitment and generation of regulatory T cells (Treg cells) which suppress inflammation, promote vascular adaptation, and foster tolerance towards fetal antigens [78]. This mechanism could shed light

VEGF, vascular endothelial growth factor.
