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Gestational Age-Dependent Expression of Insulin-Like Growth Factor-Binding Protein-1 (IGFBP-1) Phosphoisoforms in Human Extraembryonic Cavities, Maternal Serum, and Decidua Suggests Decidua as the Primary Source of IGFBP-1 in these Fluids during Early Pregnancy¹

Department of Gynecology and Obstetrics (N.A.M., E.K., U.C., L.C.G.), Stanford University Medical Center, Stanford, California 94305-5317; and Department of Reproductive Physiology (N.C.W., T.C.), St. Bartholomew’s Hospital, London, EC1A 7BE United Kingdom.

Address all correspondence and requests for reprints to: Linda C. Giudice, M.D., Ph.D., Chief, Division Reproductive Endocrinology and Infertility, Department of Gynecology and Obstetrics, Stanford University Medical Center, Room HH-333, Stanford, California 94305-5317. E-mail: giudice{at}stanford.edu

The insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are important regulators of fetal and maternal tissue development during pregnancy. Posttranslational modification of IGFBP-1 yields up to six IGFBP-1 phosphovariants and a nonphosphorylated form, which in vitro, have some different properties. Nonphospho IGFBP-1 has less affinity for IGFs than the phospho isoforms and also may have IGF-independent actions. Herein, we have investigated the complement of IGFBP-1 phosphoisoforms present in extraembryonic coelomic (EEC) fluid, amniotic fluid (AF), and maternal serum (MS) throughout human gestation. Also, to determine potential tissue source(s) of IGFBP-1 in these fluids, we have quantified IGFBP-1 and examined IGFBP-1 phosphoisoforms in conditioned media (CM) from maternal decidua, fetal liver, and fetal kidney explants throughout gestation. Western immunodetection revealed that IGFBP-1, present in EEC and AF in early pregnancy and in CM from early pregnancy decidua, is primarily in the nonphosphorylated form. MS in this period contains primarily the nonphospho form and, as in nonpregnant adults, the highly phosphorylated form of IGFBP-1. The phosphorylation profile of IGFBP-1 in AF, MS, and decidua CM changes as pregnancy progresses. All the IGFBP-1 phosphoisoforms ultimately are produced by decidua and are present in midgestation MS, and all but the most highly phosphorylated form are present in AF. In late gestation, MS contains primarily the highly phosphorylated form. In contrast, profiles in CM from explants of fetal liver and kidney at different gestational ages remain unchanged. Nonphosphorylated IGFBP-1 is the primary form in fetal kidney CM, whereas fetal liver CM contains all IGFBP-1 phosphoisoforms. Concentrations of IGFBP-1 in fetal liver and kidney CM are significantly lower (482 ± 146 and 120 ± 32 ng/mL·100 mg wet wt tissue, respectively) than in decidua CM (11,417 ± 2,358 ng/mL·100 mg wet wt tissue). The data cumulatively suggest that maternal decidua is the primary source of IGFBP-1 in EEC, AF, and MS in early pregnancy and that fetal liver and kidney are not likely significant contributors. The presence of nonphospho IGFBP-1 in AF, EEC, and MS suggests an important role for this isoform during early gestation.

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