Progesterone‐Regulated Endometrial Factors Controlling Implantation

Abstract

The steroid hormone progesterone (P), acting via the progesterone receptor (PR) isoforms, PR-A and PR-B, exerts a profound influence on uterine functions during early gestation. In recent years, chromatin immunoprecipitation-sequencing in combination with microarray-based gene expression profiling analyses have revealed that the PR isoforms control a substantially large cistrome and transcriptome during endometrial differentiation in the human and the mouse. Genetically engineered mouse models have established that several PR-regulated genes, such as Ihh, Bmp2, Hoxa10, and Hand2, are essential for implantation and decidualization. PR-A and PR-B also collaborate with other transcription factors, such as FOS, JUN, C/EBPβ and STAT3, to regulate the expression of many target genes that function in concert to properly control uterine epithelial proliferation, stromal differentiation, angiogenesis, and local immune response to render the uterus ‘receptive’ and allow embryo implantation. This review article highlights recent work describing the key PR-regulated pathways that govern critical uterine functions during establishment of pregnancy.

Forkhead box a2 (FOXA2) is essential for uterine function and fertility

“…Successful implantation requires a competent blastocyst and a receptive uterus (2,3,6). Attainment of uterine receptivity involves cell-specific actions of the steroid hormones estrogen and progesterone via their nuclear receptors (4,5,31,32).…”

“…In mice, the uterus becomes receptive to blastocyst implantation on gestational day (GD) 4 (with the observation of a postcoital vaginal plug designated GD 0.5); it is prereceptive on GD 1-3, and by the afternoon of GD 5 it becomes nonreceptive (refractory) (1)(2)(3). Dynamic changes in ovarian estrogen and progesterone production act via the uterus to regulate uterine receptivity, blastocyst implantation, and stromal cell decidualization necessary for the establishment of pregnancy (4)(5)(6). The implantation process, which is initiated by the attachment of the blastocyst trophectoderm to the receptive LE, occurs before or right after midnight in the evening of GD 4 and becomes more prominent by the morning of GD 5.…”

Hormone dependent uterine epithelial-stromal communication for pregnancy support

“…The mechanisms by which ESR1 and PGR regulate the ability of the uterus to support pregnancy has been investigated in vivo by utilizing genetically engineered mouse models [11–14]. The genes associated with uterine function to establish pregnancy have been extensively reviewed [7, 15–20]. Here, we will discuss the process of uterine receptivity and how genetically engineered mouse models have helped to identify the molecular mechanisms governing the ability of the uterus to support pregnancy, mainly based on our previous findings.…”

Progesterone Receptor Signaling in Uterine Myometrial Physiology and Preterm Birth

“…PGR is expressed in the central nervous system, ovaries, breasts, and the female reproductive tracts, including the vagina, cervix, fallopian tubes and uterine endometrium and myometrium. PGR is important for female sexual behavior, ovulation, the establishment and maintenance of pregnancy and development of mammary gland (Bhurke et al, 2016; Diep et al, 2015). In uterine myometrium, P4 signaling maintains uterine quiescence by suppressing prostaglandin and oxytocin dependent inflammatory responses and contractile activities before term.…”

“…At term, in a species dependent manner, either withdrawal of P4 by a decrease in hormone levels or alteration of PGR signaling relieves the suppression on inflammation and contraction, which allows the myometrium to adopt a contractile phenotype for laboring. Multiple mechanisms, including P4 metabolism, regulation of PGR gene expression, PGR post-translation modifications and PGR coregulators, that mediate or regulate uterine P4/PGR signaling have been identified and reviewed extensively (Bhurke et al, 2016; Grimm et al, 2016; Patel et al, 2015; Renthal et al, 2015; Rubel et al, 2016; Szwarc et al, 2014). Here we focus on discussing uterine P4/PGR signaling modifiers and effectors in myometrial physiology and diseases.…”