Serum relaxin levels are reduced in pregnant women with a history of recurrent miscarriage, and correlate with maternal uterine artery Doppler indices in first trimester

Objectives: Defective implantation is a mechanism for recurrent pregnancy loss (RPL). We sought to determine whether the serum expression of human relaxin-2 (RLX) is impaired in women with a history of RPL. Study design: Employing a prospective case-controlled design we studied 20 pregnant women with a history of RPL and 20 age-matched women with no history of RPL (NRPL). We measured serum relaxin-2 levels by ELISA at 6-8. 10-12, 20, and 34 weeks gestation and in cord blood, and maternal uterine artery Doppler resistance index (RI) at >= 10 weeks gestation. Results: Relaxin rose to a peak at 12 weeks, and gradually declined towards term. At all gestations, women with a history of RPL had lower RLX levels than women without. At 10-12 weeks gestation, uterine artery RI correlated with serum RLX for both RPL and NRPL. In the NRPL group at 10-12 weeks the presence of a notched waveform was associated with higher RLX levels than the absence of a notch (mean 2.1 ng/ml vs. 1.3 ng/ml, P < 0.05) and also at 20 weeks (2.1 ng/ml vs. 0.95 ng/ml, P < 0.05) but no such difference was seen in the RPL group. Umbilical venous RLX was 4-fold higher in the RPL group than the NRPL group. Conclusion: Women with a history of RPL demonstrate attenuated levels of serum RLX across all pregnancy trimesters. How dysregulated RLX metabolism may contribute to adverse pregnancy outcome in RPL requires further investigation. Crown Copyright (C) 2009 Published by Elsevier Ireland Ltd. All rights reserved

Human relaxin, prolactin and placental lactogen in human intrauterine tissues

Thesis (Ph. D.)--University of Hawaii at Manoa, 1991.Includes bibliographical references (leaves 142-162)Microfiche.xv, 162 leaves, bound ill. (some col.) 29 cmThe human placenta, fetal membranes and decidua can be classified as endocrine glands because of their abilities to produce hormones which maintain and ensure the success of a pregnancy. These hormones may enter the maternal and/or the fetal circulatory systems to act upon distant targets while others may be produced and act locally within the intrauterine compartment. This study was designed to look at three circulatory hormones, relaxin, prolactin and placental lactogen, as bipolar hormones, local and distant. The sources of their production were studied in five different intrauterine tissues at two physiological time frames, before and after labor. The corpus luteum is the source of circulating relaxin during pregnancy. To determine whether this hormone is produced locally in intrauterine tissues, two techniques have been used, immunocytochemistry and Northern analyses. An antiserum to a synthetic l4-amino acid sequence of the connecting peptide of human relaxin and two monoclonal antibodies to human relaxin were used to immunostain fetal membranes with adherent decidua and placental trophoblast. Poly(A)+RNA prepared from five separate tissues, the amnion, chorionic membrane, decidua parietalis , basal plate and the placental trophoblast were hybridized to a 48-mer oligoprobe to human relaxin. Results from both techniques showed that the decidua parietalis and basalis, the chorion and the placental trophoblast synthesize and produce relaxin. The mRNA species in the placental trophoblast was shown to be 1.1kb, about 100 base pairs smaller than the mRNA species in other tissues, suggesting different processing mechanisms for these two mRNA species for relaxin. Comparative quantitation of mRNA levels showed that the decidua parietalis expressed the gene for relaxin more than the other tissues. Also all tissues obtained after normal spontaneous delivery had a lower capability for relaxin synthesis than tissues obtained from term elective Cesarean section. It is generally accepted that the decidua parietalis is the primary source of amniotic fluid prolactin. Whether this hormone is a product of other intrauterine tissues has not been thoroughly defined. Two polyclonal and four monoclonal antibodies were used to localize human prolactin (hPRL) in human intrauterine tissues. Northern analyses using a 48-mer oligoprobe and a 712 base pair cDNA probe for hPRL were performed to distinguish synthesized from sequestered hormone. Results showed that the decidua parietalis is indeed the major source of amniotic fluid prolactin and that the chorion laeve and the basal plate are additional sources. There was no significant difference in hPRL mRNA levels between Cesarean section and normal vaginal delivery tissues. Human placental lactogen (hPL) is one of the major hormones secreted by the placental syncytiotrophoblast and is readily detected in the maternal circulation. In this study, a specific polyclonal antibody to hPL, a 48-mer oligoprobe and a 540 base pair cDNA probe to hPL were used to investigate and determine other possible intrauterine sources of this hormone. Results showed unequivocally that the syncytiotrophoblast is the classical source of hPL. In addition, some cells of the chorionic cytotrophoblast and the basal plate also synthesized hPL. Quantitative analysis on Northern blots showed that the mRNA levels for hPL in these extra-sources were less than one percent of that in the classical source syncytiotrophoblast. It is not known whether these small amounts of hPL by these ectopic sources stay and function locally in the intrauterine tissues or whether they contribute to maternal circulation. The differential production of the three hormones by intrauterine tissues presented in this dissertation provide further definition of a paracrine/autocrine system within these tissues

Evidence of a limited contribution of feto-maternal interactions to trophoblast differentiation along the invasive pathway

Trophoblast differentiation is a key event in human placental development. During extravillous trophoblast (EVT) differentiation, stem cells from the anchoring villi detach from their basement membrane and proliferate to form aggregates called trophoblast cell columns (TCCs). They subsequently invade the decidua and differentiate into interstitial and endovascular trophoblasts. The influence of the decidua on EVT differentiation is controversial. We therefore compared the pattern of trophoblast differentiation marker expression in viable intrauterine and tubal pregnancies, as decidual cell markers (prolactin [PRL] and insulin-like growth factor binding Protein-1 [IGFBP1]) were only expressed in endometrial implantation sites. Extravillous trophoblast differentiation in anchoring villi from uterine and ectopic pregnancies exhibited a comparable phenotypical switch: alpha6 integrin subunit, E-cadherin, EGF receptor, Ki 67 and connexin 40 were localized in the proximal part of the TCC, while alpha5beta1 and alpha1 integrins, c-erb B2, hPL and HLA-G were expressed by invasive cytotrophoblasts. The cyclin-dependent kinase inhibitors p16 and p57 were mainly detected in invasive cytotrophoblasts some distance from the columns. However, the TCC was markedly longer in tubal pregnancy than in intrauterine pregnancy. These findings suggest that the decidua is not necessary to trigger EVT invasion, but that it is likely to limit the extent of the TCC and to accelerate the onset of EVT migration