Biology of progesterone action during pregnancy recognition and maintenance of pregnancy

Progesterone is the hormone of pregnancy and unequivocally required in all mammals for maternal support of conceptus (embryo/fetus and associated membranes) survival and development. The actions of progesterone are mediated by the progesterone receptor (PR). However, the endometrial lumenal (LE) and glandular epithelia (GE) of a number of species exhibit a loss of PR expression prior to the stages of uterine receptivity and implantation. In sheep, PR expression becomes undetectable in the endometrial LE after Day 11 and then in the GE after Day 13. Loss of PR in the GE appears to be required for onset of differentiated functions in terms of production of secretory proteins, such as uterine milk proteins (UTMP) and osteopontin (OPN). Therefore, the actions of progesterone on endometrial epithelia during most of gestation appear to be mediated by the endometrial stroma that remains PR-positive throughout pregnancy. Stromal cells produce several growth factors, such as hepatocyte growth factor (HGF) and fibroblast growth factors-7 and -10 (FGF-7, FGF-10), that have receptors expressed specifically in the endometrial epithelia. These factors may be progesterone-responsive and mediate epithelial-mesenchymal interactions that are crucial for support of pregnancy. Studies of the uterine gland knockout (UGKO) ewe indicate that uterine glands and, by default, their secretions are required for peri-implantation conceptus survival and growth. A complex servomechanism, involving hormones from the ovary and conceptus as well as endogenous betaretroviruses expressed in the endometrial LE and GE, is proposed to regulate endometrial gland differentiation and function during gestation. At estrus, estrogen increases PR expression in the endometrial epithelia. High levels of endogenous Jaagsiekte sheep retroviruses (enJSRVs) are expressed in the PR-positive endometrial LE and GE in response to increasing progesterone and are hypothesized to stimulate trophoblast proliferation and production of interferon (IFN) tau. IFN tau, the pregnancy recognition hormone produced by the trophoblast from Days 10 to 21, acts in a paracrine manner on the PR-negative endometrial LE and superficial GE to inhibit transcription of estrogen receptor alpha (ER) and oxytocin receptor (OTR) genes. These actions of IFN tau maintain progesterone production from the corpus luteum by abrogating release of luteolytic pulses of prostaglandin F2 alpha (PGF) from the endometrial epithelium. The antiluteolytic effects of IFN tau are dependent on progesterone. Progesterone stimulation over 8-10 days suppresses expression of the PR gene in the LE and then GE. Loss of the PR in the LE is concomitant with decreases in mucin glycoprotein one (MUC-1), an inhibitor of blastocyst implantation. As the conceptus begins implantation on Day 15, the binucleate trophectodermal cells then differentiate and produce placental lactogen (PL), a member of the prolactin (PRL) and growth hormone (GH) family. PL stimulates GE proliferation and production of secretory proteins, such as UTMP and OPN. Interestingly, the effects of PL on the GE appear to require the absence of PR and prior exposure to IFN tau. During mid-pregnancy, the mononuclear trophectodermal cells produce GH that can also act on a progestinized uterus to stimulate GE hypertrophy and secretory function. The actions of this servomechanism are proposed to stimulate GE hyperplasia from Days 20 to 50 and then GE hypertrophy and maximal differentiated function after Day 50 when the majority of fetal growth and development occurs during gestation.