90 YEARS OF PROGESTERONE: New insights into progesterone receptor signaling in the endometrium required for embryo implantation

Abstract

Progesterone's ability to maintain pregnancy in eutherian mammals highlighted this steroid as the 'hormone of pregnancy'. It was the unique 'pro-gestational' bioactivity of progesterone that enabled eventual purification of this ovarian steroid to crystalline form by Willard Myron Allen in the early 1930s. While a functional connection between normal progesterone responses ('progestational proliferation') of the uterus with the maintenance of pregnancy was quickly appreciated, an understanding of progesterone's involvement in the early stages of pregnancy establishment was comparatively less well understood. With the aforementioned as historical backdrop, this review focuses on a selection of key advances in our understanding of the molecular mechanisms by which progesterone, through its nuclear receptor (the progesterone receptor), drives the development of endometrial receptivity, a transient uterine state that allows for embryo implantation and the establishment of pregnancy. Highlighted in this review are the significant contributions of advanced mouse engineering and genome-wide transcriptomic and cistromic analytics which reveal the pivotal molecular mediators and modifiers that are essential to progesterone-dependent endometrial receptivity and decidualization. With a clearer understanding of the molecular landscape that underpins uterine responsiveness to progesterone during the periimplantation period, we predict that common gynecologic morbidities due to abnormal progesterone responsiveness will be more effectively diagnosed and/or treated in the future.

Keywords: decidualization; endometrium; isoforms; mediators; modifiers; nuclear receptor; progesterone; receptivity.

Figure 1

Functional domain organization of the human progesterone receptor. The progesterone receptor (PGR), a member of the NR3C3 subfamily of the nuclear receptor superfamily (Mangelsdorf et al. 1995; Tsai and O’Malley 1994), is comprised of two isoforms: the full-length PGR-B and the truncated PGR-A; the same gene—located on human chromosome 11 (11q22-q23)—encodes both isoforms. The N-terminal domain (NTD), DNA binding domain (DBD), hinge (H) region, and ligand binding domain (LBD) are indicated. The positions of activation functional domains (AF1, AF2, and AF3) are shown; note: the PGR-A isoform lacks AF-3 and multiple phosphorylation events. Phosphorylation sites are denoted by (P); locations of sumoylation, acetylation and methylation sites are also highlighted. Detailed information on these PTMs is comprehensively described in previous excellent reviews, such as (Diep et al. 2015; Grimm et al. 2016; Hagan and Lange 2014). The schematic was reproduced and modified from (Grimm et al. 2016) with permission from the Journal of Molecular Biology (license number: 4591510498146).

Figure 2

A propensity for complexity: molecular signaling required for progesterone-dependent uterine receptivity and decidualization. (A) The progesterone-PGR-IHH-COUP-TFII signaling pathway, which spans the epithelial and stromal cellular compartments of the endometrium, controls ESR1 activity in the endometrial epithelium. Such ESR1 control is required for epithelial differentiation and development of the receptive endometrium for embryo implantation. For clarity, other signals (i.e. Msx 1 and 2), which are important for uterine receptivity, are not be included in this schematic. (B) A selection of progesterone-induced signaling pathways required for endometrial stromal cell decidualization during the periimplantation period. Adapted with permission in modified form from (Wu, et al. 2018).

Figure 3

Progesterone receptor and FOXO1 display a “Yin Yang” expression relationship in the epithelium of the murine endometrium during the window of implantation. (A) Robust luminal epithelial (LE) expression of FOXO 1 (brown arrowhead) in the uterus of a control mouse (Foxo1^f/f) at day 4.5 of pregnancy (the morning of vaginal plug detection is designated pregnancy day 0.5). (B) Serial section of uterine tissue shown in (A) stained for PGR. As expected (Wetendorf et al. 2017), note the absence of PGR expression in the luminal epithelium (blue arrowhead) with marked expression in the stroma. (C) Staining for FOXO1 expression in the uterus of a Foxo1^d/d mouse at 4.5 days following the detection of the vaginal plug. Unlike control uterus (A), note the clear absence of FOXO1 expression in the luminal epithelium (blue arrowhead) in the Foxo1^d/d uterus. (D) Staining for PGR expression in a serial section of uterine tissue shown in (C) reveals abnormal constitutive PGR expression in the luminal epithelium (brown arrowhead) in the Foxo1^d/d uterus. (E) The immunohistochemical findings shown in (A-D) are schematically summarized as a proposed model for the suppression of PGR expression in the endometrial luminal epithelium by FOXO1 within the window of receptivity. The immunohistochemical data shown in panels (A-D) and the modified schematic model shown in (E) are presented in adapted form from (Vasquez et al. 2018).