Placental Steroids in Cattle: Hormones, Placental Growth Factors or By-products of Trophoblast Giant Cell Differentiation?

Abstract

The bovine placenta produces large amounts of steroids, mainly estrone (E1) and progesterone (P4). Specific features of bovine placental steroidogenesis are 1) the expression of all enzymes needed for the production of estrogens from cholesterol in the trophoblast 2) an only marginal and temporal contribution to peripheral maternal P4 levels restricted to a period between approx. days 150 - 240 of gestation 3) the predominance of sulfoconjugated over free E1 and 4) a complementary setting of steroidogenic enzymes in the two morphologically discriminable trophoblast cell types, the uninucleated trophoblast cells (UTC) and the trophoblast giant cells (TGC). In cattle so far no definite information is available on the specific biological roles of placental estrogens and P4. However, the detection of estrogen receptors and progesterone receptors in the placentomes suggests a role primarily as local regulators of caruncular growth, differentiation and functions. Inconsistent with a function as a caruncular growth factor is the strong evidence that in cattle placental estrogens enter the maternal compartment almost completely as estrone sulfate (E1S), which is not active at classical nuclear receptors. On the other hand, E1S may be converted locally to free active estrogens via the action of steroid sulfatase (StS), which has been detected in specific parts of the bovine caruncular epithelium. Alternatively or in addition, StS expression in the caruncular epithelium may serve the utilization of sulfated neutral steroid precursors (e.g. pregnenolone sulfate or cholesterol sulfate) supplied with maternal blood, thus providing free substrates for further metabolization in the adjacent trophoblast. The down-regulation of P450scc and P450c17 and the up-regulation of 3beta-HSD and aromatase during the differentiation of TGC from UTC in parallel with the up-regulation of ER beta and estrogen sulfotransferase in maturing TGC suggests a function of placental estrogens primarily as autoor intracrine regulators during this process and assigns to conjugated placental estrogens a role as inactivated by-products of TGC differentiation intended for excretion. Collectively, despite some evidence from recent studies for putative roles of placental steroids in cattle their exact functions in the bovine species remain still undefined.

Investigations into the mechanisms controlling parturition in cattle

“…This assumption needs further confirmation but is not consistent with our previous in vitro results on placental steroid metabolism, suggesting that also in the bovine placenta a pronounced prepartal switch of placental steroidogenesis from progesterone to estrogens occurs (Schuler et al 1994). However, different from placental homogenates, under in vivo conditions in the bovine trophoblast, steroidogenic enzymes are clearly compartmentalized at a cellular level, possibly effecting a different substrate flow under in vivo conditions (Schuler et al 2008).…”

Multilevel regulation of steroid synthesis and metabolism in the bovine placenta

“…The foetal cotyledon is also the primary site of P450c17 and P450arom localization, the key enzymes for the synthesis of oestrogens (Tsumagari et al, 1993;Schuler et al, 2006a). P450c17 is present exclusively in the UTCs, but is down-regulated when these cells differentiate into TGCs; P450arom level, on the other hand, increases as UTCs differentiate to TGCs (Schuler et al, 2008). Thus, the synthesis of androgens (androstenedione and testosterone) is partitioned to the UTCs while the synthesis of oestrogens (oestrone and oestradiol) is partitioned to the TGCs (Fig.…”

“…The rapid downregulation of P450scc and upregulation of 3b-HSD when the UTCs differentiate into the TGCs (Fig. 5) is a possible way to temporally regulate progesterone synthesis in coordination with cellular differentiation (Schuler et al, 2008). It was also suggested that TGCs do not synthesize progesterone until they migrate to the maternal caruncular epithelium, where they then contribute to progesterone in maternal blood, thereby sequestering progesterone away from foetal blood (Reimers et al, 1985).…”

“…The production of steroid hormones in this organ is regulated, in part, by altering the relative levels and tissuespecific localization of different steroidogenic enzymes. Yet, it remains unclear whether the expression levels of the steroidogenic enzymes are intrinsically programmed along with placental cell differentiation during pregnancy or are regulated by cross-talk between the different placental tissues/cell-types (Schuler et al, 2008). Because progesterone and oestrogen receptors are found in caruncular, stromal, and epithelial cells during the second half of gestation, it is suggested that placental progesterone and oestrogens act as paracrine factors, mediating the local regulation of caruncular growth, differentiation and function Hoffmann and Schuler, 2002;Schuler et al, 2002).…”

“…5). As in the case of progesterone synthesis, the coordination of the synthesis of oestrogens can be accomplished by both the spatial diffusion of steroid substrates from UTCs to TGCs, and the temporal change in the expression of steroidogenic enzymes when UTCs differentiate into TGCs (Schuler et al, 2008).…”