A link between high serum levels of human chorionic gonadotrophin and chorionic expression of its mature functional receptor (LHCGR) in Down's syndrome pregnancies

Abstract

Human chorionic gonadotrophin (hCG) is released from placental trophoblasts and is involved in establishing pregnancy by maintaining progesterone secretion from the corpus luteum. Serum hCG is detected in the maternal circulation within the first 2-3 wks of gestation and peaks at the end of the first trimester before declining. In Down's syndrome (DS) pregnancies, serum hCG remains significantly high compared to gestation age-matched uncompromised pregnancies. It has been proposed that increased serum hCG levels could be due to transcriptional hyper-activation of the CGB (hCG beta) gene, or an increased half life of glycosylated hCG hormone, or both. Another possibility is that serum hCG levels remain high due to reduced availability of the hormone's cognate receptor, LHCGR, leading to lack of hormone utilization. We have tested this hypothesis by quantifying the expression of the hCG beta (CGB) RNA, LHCGR RNA and LHCGR proteins in chorionic villous samples. We demonstrate that chorionic expression of hCG beta (CGB) mRNA directly correlates with high serum hCG levels. The steady-state synthesis of LHCGR mRNA (exons 1-5) in DS pregnancies was significantly higher than that of controls, but the expression of fulllength LHCGR mRNA (exons 1-11) in DS was comparable to that of uncompromised pregnancies. However, the synthesis of high molecular weight mature LHCGR proteins was significantly reduced in DS compared to uncompromised pregnancies, suggesting a lack of utilization of circulating hCG in DS pregnancies.

Genetic recapitulation of human pre-eclampsia risk during convergent evolution of reduced placental invasiveness in eutherian mammals

“…Diseases exhibiting significant genetic overlap with the set of 1254 genes subject to adaptive evolution during evolutionary transitions towards less-invasive forms of placentation in kangaroo rats, strepsirhine primates and tree shrews; significance reported as Benjamini -Hochberg adjusted q-value. [45], as well as numerous other signalling pathways associated with placentation and placental disease including fibroblast growth factor and interferon gamma [46,47]. Statistical identification of gene clusters enriched in common between adaptively evolving genes and combined pre-eclampsia-associated genes yielded similar results (electronic supplementary material, tables S6 and S8) confirming the pre-eclampsia associations of these processes and pathways.…”

Quantitative ELISAs for serum soluble LHCGR and hCG-LHCGR complex: potential diagnostics in first trimester pregnancy screening for stillbirth, Down’s syndrome, preterm delivery and preeclampsia

“…The specificity of LHR29 antibody was established by immunoprecipitation and immunopurification of 125 IhCG-LHCGR complex, western blot analysis of the immunogen [17] and LHCGR ECD (amino acids 1–362) expressed in HEK 293 cells [18] and Dr Axel Themmen, personal communication.…”

“…USA), only mature (M r 85-90K) and M r 50K bands reacted with 125 I-hCG (19). None of these bands reacted when the primary antibody was replaced by isotype-specific mouse IgG [18] and data not shown. Therefore, at the initial phase of this study LHR29 and PG732 were used as capture and detection antibodies, respectively, in ELISA for LHCGR measurement.…”

Circulating LH/hCG receptor (LHCGR) may identify pre-treatment IVF patients at risk of OHSS and poor implantation

“…Notably, a recent report suggests hCG stimulates LHCGR expression in lymphocyte during controlled ovarian stimulation and is linked to improved implantation [32] On the other hand, undetectable to low circulating sLHCGR/LH-sLHCGR might reflect reduced hormonal activation and down regulation of sLHCGR synthesis as observed in Down's syndrome placenta [33,34]. This may suggest that like other cytokine and hormone receptors [27-30], the production of sLHCGR is regulated.…”