Molecular Human Reproduction, Vol. 5, No. 10, 895-897,
October 1999
© 1999 European Society of Human Reproduction and Embryology
Debate |
What factors regulate HCG production in Down's syndrome pregnancies?
Regulation of HCG during normal gestation and in pregnancies affected by Down's syndrome
Department of Obstetrics and Gynecology, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria
Human chorionic gonadotrophin (HCG), a placentally-derived hormone, is required for successful maintenance of human pregnancy. Classically, rescue of the corpus luteum until the luteal–placental shift in progesterone synthesis occurs, is regarded as its major role (Hussa, 1980
). Maternal serum concentrations of HCG rapidly increase during the first trimester, peak at weeks 9–10, and fall to a low plateau after the 20th week of pregnancy (Braunstein et al., 1976). During the second trimester, elevated serum concentrations of HCG are known to be associated with different complications of euploid pregnancies as well as with chromosomal abnormalities of the fetus, e.g. Down's syndrome (Bogart et al., 1989; Gonen et al., 1992; Benn et al., 1996). Therefore, the hormone has become one of the biochemical screening tests which are routinely offered in clinics (Haddow et al., 1992, 1998). Despite this, however, little is known about the mechanisms which control HCG synthesis throughout uncomplicated pregnancies, and the cause of aberrant concentrations of HCG in abnormal gestations remains enigmatic.
Several concepts were developed to explain the extraordinary expression pattern of HCG, which is predominantly governed by the rate of synthesis of its specific ß-subunit (Vaitukaitis et al., 1976). Some authors postulated that the increase in HCG was related to the morphological changes taking place in early pregnancy, and speculated that trophoblast invasion of maternal tissue, blood flow in the intervillous space and amnion–chorion fusion could play a role in increasing and decreasing HCG concentrations (Chard et al., 1993, 1995). At the cellular level, multiple factors have been identified (Petraglia, 1991; Merz, 1994), which may modulate HCG production by interaction with specific surface receptors of the placental trophoblast (the principle source of the hormone). Amongst these, gonadotrophin-releasing homone (GnRH) has attracted some interest, since the expression profile of its receptor is similar to that of HCG (Lin et al., 1995). In addition, HCG expression appears to be regulated by an autocrine feedback loop, since binding of the hormone to the HCG receptor of the trophoblast down-regulates its own synthesis (Licht et al., 1993). Hence serum concentrations of HCG may depend on the developmental status of paracrine and autocrine growth factors, as well as receptors expressed on the placental trophoblast.
Small amounts of the hormone are stored intracellularly and trophoblast-specific production is thought to be mainly triggered by transcriptional activation of 
HCG and ßHCG genes (Milsted et al., 1987; Bo and Biome, 1992). Using choriocarcinoma cells as a model system, several investigators described the regulatory DNA sequences required for inducible and cell-specific HCG gene expression (Hollenberg et al., 1994; Budworth et al., 1997). Both the HCG promoter and the 5' regulatory sequences of ßHCG genes can be activated by cAMP-dependent signal transduction (Delegeane et al., 1987; Fenstermaker et al., 1989), the second messenger cascade of diverse growth factors. With respect to HCG gene expression, similar transcriptional activators which mediate the cAMP response were identified in tumour cells and differentiating cytotrophoblast cultures (Heckert et al., 1996; Knöfler et al., 1999). Co-ordinate activation of HCG subunits might be established by a trophoblast-specific transcription factor which is likely to be a member of the family of AP-2 proteins and interacts with a common motif in the and HCGß5 promoter (Steger et al., 1993; Johnson et al., 1997). Interestingly, sequences have been identified which silence both subunit promotors in the presence of Oct3/4, and which may suppress HCG synthesis in vivo in the inner cell mass and may allow for early onset of hormone production in trophoectodermal cells (Liu and Roberts, 1996; Liu et al., 1997).
In-vivo expression of HCG is associated with formation of villous syncytiotrophoblasts (Hoshina et al., 1982), a process which can be studied in vitro on isolated cytotrophoblast cells of term placenta (Kliman et al., 1986). During this differentiation, discordant induction of and ßHCG was observed, suggesting that production of ßHCG is more strictly dependent on syncytium formation (Kato and Braunstein, 1989; Ringler et al., 1989). However, there is also evidence that cytotrophoblasts express abundant amounts of HCG prior to the sixth week of pregnancy (Maruo et al., 1992). This is also reflected by high concentrations of the hormone in first trimester cultures (Eldar-Geva et al., 1995). At present, it is unclear whether similar or different regulatory mechanisms control HCG production in the diverse trophoblast cell types. Since ßHCG expression was also identified in the secretory phase of the cyclic endometrium (Wolkersdorfer et al., 1998), further studies are required to elucidate the function and regulation of this hormone in pregnant and non-pregnant women.
What can be concluded from the complex regulation of HCG with respect to its abnormal expression in Down's pregnancies? Although the gene dosage effect (Goshen, 1999) of the extra chromosome may represent an attractive model, there is evidence that elevated HCG concentrations could be explained by the immature stage of the placental cytotrophoblast (Chard, 1991). Indeed, placentae from Down's syndrome pregnancies contain a hypoblastic trophoblast layer which comprises residual cytotrophoblasts (Hustin and Jauniaux, 1992). Since these aneuploid villi show reduced vascularization and stromal oedema it was suggested that the appearance of the trophoblasts could be secondary to the abnormal umbilical blood flow of the fetus (Jauniaux and Hustin, 1998). Thus, elevation of HCG could be a more general phenomenon related to, for example, the unfavourable supply of growth factors preventing formation of syncytiotrophoblasts or promoting degeneration of these cells.
On the other hand, in-vitro differentiation of cytotrophoblasts to syncytiotrophoblasts seems to be HCG-dependent. Low concentrations of HCG promote cellular aggregation and HCG receptor expression while high doses of the hormone have the opposite effect (Shi et al., 1993). Interestingly, cytotrophoblasts from Down's syndrome placentae producing elevated amounts of HCG are less capable of forming syncytia in vitro, than their normal counterparts (Eldar-Geva et al., 1995). One may speculate that, independent of HCG expression, a failure in trophoblast differentiation has occurred. Higher concentrations of HCG could then be explained by immaturity of the cytotrophoblasts, which are unable to form syncytia and to down-regulate their own hormone synthesis. Alternatively, one may assume that up-regulation of HCG, for example, by a putative transcription factor of the extra chromosome 21, may result in suppression of cell fusion.
Moreover, if such a transactivation factor exists, it is questionable whether it would be a useful tool for the prenatal diagnosis of Down's syndrome. Due to the presence of only one additional copy of the gene, one would have to quantify a 1.5-fold increase in a mRNA/protein, present only at low concentrations, the expression of which may vary throughout gestational age and between samples of chorionic villi. Appropriate normalization controls, which are not affected by the disease, would be needed to measure the minor differences in mRNA/protein abundancies. Thus, quantification of such genes will probably not increase the detection rate of Down's syndrome pregnancies. More likely, improvement of novel techniques to directly quantify DNA markers of the extra chromosome, e.g. by fluorescent polymerase chain reaction (PCR) (Findlay et al., 1998; Toth et al., 1998), will eventually reduce the time and costs of early screening for Down's syndrome.
Acknowledgments
I would like to thank Heinz Strohmer for helpful discussion and Markus Wolschek for critical reading of the article. M.K.'s research on trophoblast function and differentiation is supported by grants Nr. 6795 and Nr. 7555 of the `Jubiläumsfond' of the Austrian National Bank and a grant from the Fonds zur Förderung der wissenschaftlichen Forschung (P12486-MED).
Notes
This debate was previously published on Webtrack 76, July 1, 1999
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