Role of Progesterone in Nonhuman Primate Implantation

Abstract

Herein we review the morphological and physiological effects of estradiol and progesterone (P) on the nonhuman primate uterus. Progesterone action acts to prepare the endometrium for embryo implantation, which normally occurs only during a brief period in the mid-luteal phase of the menstrual cycle. During this window of implantation, P stimulates secretory morphological differentiation and suppresses estrogen receptor alpha (ERalpha), in the endometrial functionalis zone. Reduced endometrial ERalpha is a definitive physiological marker for the onset of endometrial receptivity in primates. These actions of P are specific for the functionalis zones, and P does not fully inhibit ERalpha in the glands of basalis zone of nonhuman primates. Paradoxically, during the secretory phase of the cycle, progesterone receptor (PR) is also reduced in the glandular epithelium of the progestin-responsive functionalis zone. Therefore, P action on the epithelium in the functionalis zone may be mediated by paracrine factors arising from the PR-positive cells in the stroma. Genomic analysis of the endometrium of women and nonhuman primates has revealed numerous secretory phase genes that may contribute to differentiation of the endometrium. However, the exact nature and function of these putative factors have been elusive. We propose that nonhuman primates, especially macaques, can provide a valuable animal model for experimentally testing the functional role of P-regulated genes on endometrial receptivity.

Comparative aspects of implantation

“…Uterine receptivity to implantation requires P 4 that is also permissive to actions of IFNs, CG (chorionic gonadotropin), and lactogenic hormones (Fazleabas 2007, Joyce et al 2007a, 2007b, Slayden & Keater 2007. The paradox is that cessation of expression of PGR and ESR1 by uterine epithelia is a prerequisite for uterine receptivity to implantation, expression of genes for secreted proteins, and selective transport of molecules into the uterine lumen that support conceptus development.…”

“…Silencing expression of PGR in uterine epithelia requires that P 4 acts via PGR-positive uterine stromal cells to induce expression of progestamedins, e.g. FGF7, FGF10, and/or HGF to exert paracrine effects on uterine epithelia and conceptus trophectoderm that express receptors for FGF7 and FGF10 (FGFR2(IIIb)) and HGF (MET; protooncogene MET; Slayden & Keater 2007). Many ISGs are P 4 -induced and IFN-stimulated; however, the mechanism whereby actions of P 4 and IFNs on uterine epithelia lacking PGR and the classical JAK/TYK2 cell-signaling mechanisms is not known.…”

“…Endocrine regulation of implantation involves a highly synchronized series of reciprocal interactions between conceptus trophectoderm and uterine endometrium during the 'window of receptivity' to implantation (see Fazleabas et al 2004, Slayden & Keater 2007. Uterine receptivity to implantation requires actions of progesterone (P 4 ) and/or estrogen on the uterus to regulate locally produced cytokines, growth factors, homeobox transcription factors, and cyclooxygenase-derived prostaglandins through autocrine and paracrine pathways.…”

“…Expression of novel genes by uterine LE and sGE is discussed in more detail in the sections on implantation in ruminants and in pigs. In species with invasive placentae, it is also true that trophectoderm cells achieve direct contact with stromal cells that produce progestamedins and/or estramedins that can directly stimulate proliferation and differentiated functions of trophoblast cells (Slayden & Keater 2007).…”

Pregnancy recognition signals in mammals: the roles of interferons and estrogens

“…Secretions from uterine GE increase in response to P4, likely acting via PGR in stromal cells that express progestamedins such as FGF7, FGF10 and HGF (Slayden and Keater, 2007). Proteins in these secretions include uteroglobin, histone A2, spermidine/spermine acetyltransferase 2, secretory leukocyte protease inhibitor and metallothionine.…”