All mammalian uteri contain endometrial epithelia that synthesize and secrete or transport a complex array of proteins and related substances termed ‘histotroph’ (Wimsatt 1950, Amoroso 1952, Bazer 1975); that is, a complex mixture of enzymes, growth factors, cytokines, lymphokines, hormones, transport proteins and other substances. Evidence from human, primate and subprimate species during the last century supports an unequivocal role for secretions of endometrium as primary regulators of conceptus survival, development, production of pregnancy recognition signals, implantation and placentation (reviewed in (Bazer et al. 1979, Roberts & Bazer 1988, Carson et al. 2000, Gray et al. 2001a, Burton et al. 2002). The microvillous epithelial cells of the uterine lumen present a high secretory activity during the luteal phase of the cycle and at the beginning of implantation (Guillomot et al. 1981). The sheep trophoblast appears to be the site of intense pinocytotic activity that increases as the blastocyst develops (Wintenberger-Torres & Flechon 1974). Therefore, it has been hypothesized that metabolites necessary for growth of the elongating conceptus are obtained from uterine histotroph. This hypothesis is supported by studies on the asynchronous transfer of embryos and trophoblast vesicles (Lawson et al. 1983, Flechon et al. 1986), but especially by results from studies of the uterine gland knockout (UGKO) ewe (Gray et al. 2001c, 2002).
The UGKO ewe model is produced by continuous administration of a synthetic, nonmetabolizable progestin to neonatal ewes from birth to at least postnatal day 56 (Gray et al. 2000a). This inappropriate exposure to a progestin permanently ablates differentiation and development of the glandular epithelia (GE) from LE in the endometrium and produces an UGKO phenotype without altering development of myometrium or other Müllerian duct-derived female reproductive tract structures or the hypothalamic–pituitary–ovarian axis (Gray et al. 2000a,b, 2001b). The endometrium is devoid of middle to deep endometrial glands and the LE surface area is markedly reduced. UGKO ewes exhibit recurrent early pregnancy loss in which the blastocyst fails to elongate. Transfer of blastocysts from normal fertile ewes into the uteri of timed recipient UGKO ewes did not ameliorate this defect (Gray et al. 2001c). Morphologically normal blastocysts are present in uterine flushes of bred UGKO ewes on days 6 and 9 after mating, but not on day 14 (Gray et al. 2001c, 2002). On day 14, uterine flushes of mated UGKO ewes contain either no conceptus or a severely growth-retarded tubular conceptus. Therefore, histotrophic secretions from the endometrial epithelia are required for peri-implantation blastocyst survival and elongation in sheep.
Available results indicate that the defects in blastocyst survival and elongation in UGKO ewes are not due to alterations in expression of steroid receptors, mucin glycoprotein 1 (MUC1) or adhesive integrins on the endometrial LE, or to the responsiveness of the endometrium to the conceptus pregnancy recognition signal IFN (Gray et al. 2000a, 2002). However, when uterine flushes of day 14 bred UGKO ewes were analyzed for the presence of osteopontin (OPN) and glycosylated cell adhesion molecule 1 (GlyCAM-1) proteins, which are adhesion proteins secreted primarily by GE (Johnson et al. 1999a, b, Spencer et al. 1999a), very low levels of OPN and GlyCAM-1 were found compared to control day 14 pregnant ewes (Gray et al. 2002). Therefore, the reduction or absence in adhesion proteins of endometrial epithelial origin is proposed as the cause of recurrent pregnancy loss in the UGKO ewe.