Conceptus signals for establishment and maintenance of pregnancy

Abstract

Establishment and maintenance of pregnancy results from signaling by the conceptus (embryo/fetus and associated extraembryonic membranes) and requires progesterone produced by the corpus luteum (CL). In most mammals, hormones produced by the trophoblast maintain progesterone production by acting directly or indirectly to maintain the CL. In domestic animals (ruminants and pigs), hormones from the trophoblast are antiluteolytic in that they act on the endometrium to prevent uterine release of luteolytic prostaglandin F2 alpha (PGF). In cyclic and pregnant sheep, progesterone negatively autoregulates expression of the progesterone receptor (PR) gene in the endometrial luminal (LE) and superficial glandular epithelium (GE). Available evidence in cyclic sheep indicates that loss of the PR is closely followed by increases in epithelial estrogen receptors (ER) and then oxytocin receptors (OTR), allowing oxytocin to induce uterine release of luteolytic PGF pulses. In pregnant sheep, the conceptus trophoblast produces interferon tau (IFN tau) that acts on the endometrium to inhibit transcription of the ER alpha gene directly and the OTR gene indirectly to abrogate development of the endometrial luteolytic mechanism. Subsequently, sequential, overlapping actions of progesterone, IFN tau, placental lactogen (PL) and growth hormone (GH) comprise a hormonal servomechanism that regulates endometrial gland morphogenesis and terminal differentiated function to maintain pregnancy in sheep. In pigs, the conceptus trophoblast produces estrogen that alters the direction of PGF secretion from an endocrine to exocrine direction, thereby sequestering luteolytic PGF within the uterine lumen. Conceptus estrogen also increases expression of fibroblast growth factor 7 (FGF-7) in the endometrial LE that, in turn, stimulates proliferation and differentiated functions of the trophectoderm, which expresses the FGF-7 receptor. Strategic manipulation of these physiological mechanisms can offer therapeutic schemes to improve uterine capacity, conceptus survival and reproductive health.

Effect of progesterone on embryo survival

“…Progesterone has been called the 'hormone of reproduction', acting through its receptor and several co-factors it orchestrates molecular, biochemical and physiological interactions in the uterus that affect embryo growth, development and viability (Spencer et al, 2004). Progesterone affects the volume of uterine secretions (Garrett et al, 1988) and the rate of conceptus development (Garrett et al, 1988;Green et al, 2005) as well as the ability of embryos to produce the luteolysis inhibitor interferon-tau (IFN-t) (Garrett et al, 1988;Kerbler et al, 1997;Mann et al, 2006) and the timing and strength of PGF2a (Mann and Lamming, 1995;Mann et al, 1998).…”

Effect of exogenous melatonin on the ovary, the embryo and the establishment of pregnancy in sheep

“…On the other hand, oestradiol and progesterone are the main modulators of uterine function, and both of them are implicated in the timing of luteolysis via their nuclear receptors (Lamming et al, 1995;Meikle et al, 2004). The embryo generates a signal (interferon-tau, IFNt) into the uterine horns during elongation, which alters uterine gene expression, modifying the episodic PGF 2a release, which is responsible for the luteal regression (review, Spencer et al (2004)). …”

Upregulation of Interferon-stimulated Genes and Interleukin-10 in Peripheral Blood Immune Cells During Early Pregnancy in Dairy Cows

“…After establishment of pregnancy in domestic ruminants, the conceptus secretes interferon-tau (IFNT) as a maternal recognition factor [4]. IFNT acts in the uterus around day 16 after insemination and prevents luteolysis by inhibiting prostaglandin F 2α release, resulting in the maintenance of corpus luteum function; therefore, this period is termed the maternal recognition period (MRP) [5]. IFNT induces the synthesis and secretion of IFN-stimulated genes (ISGs) such as ISG15, 2′,5′-oligoadenylate synthetase (OAS-1), IFN regulatory factor 1, Mx1 and Mx2 not only in the uterus but also in blood cells in ewes and cows [6][7][8][9][10].…”