Minireview: Steroid-regulated paracrine mechanisms controlling implantation

Abstract

Implantation is an essential process during establishment of pregnancy in mammals. It is initiated with the attachment of the blastocyst to a receptive uterine epithelium followed by its invasion into the stromal tissue. These events are profoundly regulated by the steroid hormones 17β-estradiol and progesterone. During the past several years, mouse models harboring conditional gene knockout mutations have become powerful tools for determining the functional roles of cellular factors involved in various aspects of implantation biology. Studies using these genetic models as well as primary cultures of human endometrial cells have established that the estrogen receptor α, the progesterone receptor, and their downstream target genes critically regulate uterine growth and differentiation, which in turn control embryo-endometrial interactions during early pregnancy. These studies have uncovered a diverse array of molecular cues, which are produced under the influence of estrogen receptor α and progesterone receptor and exchanged between the epithelial and stromal compartments of the uterus during the progressive phases of implantation. These paracrine signals are critical for acquisition of uterine receptivity and functional interactions with the embryo. This review highlights recent work describing paracrine mechanisms that govern steroid-regulated uterine epithelial-stromal dialogue during implantation and their roles in fertility and disease.

Figure 1.

Steroid-mediated glandular epithelial-luminal epithelial-stromal cross talk in the uterus. E induces LIF in the glandular epithelium (blue), which acts in a paracrine manner on the luminal epithelium (purple) to activate the JAK/STAT pathway to mediate a shift in junctional integrity required for implantation. Activation of JAK/STAT also promotes proliferation of the stroma (pink) via expression and secretion of EGF family proteins from the luminal epithelium. Dashed lines represent indirect events. LIFR, LIF receptor; EGFR, EGF receptor.

Figure 2.

Steroid-mediated luminal epithelial-stromal cross talk in the uterus. P drives IHH expression in the luminal epithelium (purple). IHH acts on the stroma to promote decidualization through activation of COUP-TFII signaling. Decidualization results in morphologically distinct stroma (green) compared with undifferentiated stroma (pale pink). Dashed lines represent indirect events.

Figure 3.

Steroid-mediated epithelial-stromal cross talk in the uterus. Before implantation, E, acting through ESR1 in the stroma (pink), drives epithelial (purple) proliferation through the secretion of paracrine acting FGFs. During the periimplantation period, P, acting on PGR in the stroma, promotes the expression of HAND2. HAND2 inhibits expression of FGFs and blocks E-induced epithelial proliferation. Dashed lines represent indirect events. FGFR, FGF receptor.

Figure 4.

Epigenetic silencing of Hand2 through hormonal dysregulation or environmental insults leads to signs of complex atypical uterine hyperplasia.