Transforming growth factor b (TGFb) superfamily members are closely associated with tissue remodelling events and reproductive processes. This review summarises the current state of knowledge regarding the expression and actions of TGFb superfamily members in the uterus, during the menstrual cycle and establishment of pregnancy. TGFbs and activin b subunits are abundantly expressed in the endometrium, where roles in preparation events for implantation have been delineated, particularly in promoting decidualisation of endometrial stroma. These growth factors are also expressed by epithelial glands and secreted into uterine fluid, where interactions with preimplantation embryos are anticipated. Knockout models and embryo culture experiments implicate activins, TGFbs, nodal and bone morphogenetic proteins (BMPs) in promoting pre-and post-implantation embryo development. TGFb superfamily members may therefore be important in the maternal support of embryo development. Following implantation, invasion of the decidua by fetal trophoblasts is tightly modulated. Activin promotes, whilst TGFb and macrophage inhibitory cytokine-1 (MIC-1) inhibit, trophoblast migration in vitro, suggesting the relative balance of TGFb superfamily members participate in modulating the extent of decidual invasion. Activins and TGFbs have similar opposing actions in regulating placental hormone production. Inhibins and activins are produced by the placenta throughout pregnancy, and have explored as a potential markers in maternal serum for pregnancy and placental pathologies, including miscarriage, Down's syndrome and pre-eclampsia. Finally, additional roles in immunomodulation at the materno-fetal interface, and in endometrial inflammatory events associated with menstruation and repair, are discussed.

No abstract

BACKGROUNDSuccessful blastocyst implantation requires the differentiation of human endometrial stromal cells (HESC), a process known as decidualization. Activin A, a transforming growth factor β (TGFβ) superfamily member, enhances HESC decidualization and localizes to decidual cells in human endometrium. Other TGFβ superfamily members, including BMP2, BMP4, BMP7, GDF5, GDF8, GDF11, TGFβs and Nodal, may also play a role during decidualization. This study aimed to identify these TGFβ family members in human endometrium, and to determine whether they are involved in human decidualization.METHODSProtein localization of TGFβ family members was examined in secretory phase human endometrium and first trimester decidua by immunohistochemistry. mRNA expression was examined in HESC. Activin inhibitors (Activin-M108A/SB431542) with differing specificities for the other TGFβ members under consideration were applied during HESC decidualization in vitro. The secretion levels of potential TGFβ superfamily members were measured during decidualization, and recombinant proteins added to examine their effect.RESULTSThis study has identified BMP2, BMP4, BMP7, GDF5, GDF8 and GDF11 but not Nodal in secretory phase human endometrium, but only BMP2, GDF5 and TGFβ1 protein were detected in decidual cells. All ligands except Nodal were expressed by cultured HESC. Both inhibitors significantly reduced decidualization validating the role of activin, but potentially also other TGFβ members, during decidualization. BMP2 and TGFβ1 secretion increased during HESC decidualisation and exogenous administration of these proteins significantly enhanced decidualization in vitro.CONCLUSIONSLike activin, BMP2 and TGFβ1 are likely to be involved in HESC decidualization. This is the first study to identify and localize BMP4, BMP7, GDF5, GDF8 and GDF11 in secretory phase human endometrium. Understanding the factors critical for the implantation process is needed for improving fertility and pregnancy outcomes.

The differentiation of endometrial stromal cells into decidual cells (decidualization) is critical for embryo implantation, but the mechanisms remain poorly defined. Numerous paracrine agents including IL-11 promote human endometrial stromal cell (HESC) decidualization. IL-11 signaling is transduced by the signal transducers and activators of transcription (STAT) proteins. Suppressors of cytokine signaling (SOCS) proteins are stimulated in response to cytokine-inducible STAT phosphorylation, acting in a negative-feedback mechanism to hinder cytokine receptor activity. This study examined the role of IL-11 signal transduction components in HESC decidualization in an ex vivo model. Cells were induced to differentiate with estrogen plus medroxyprogesterone acetate (E+P) or cAMP (assessed by prolactin secretion) and resulted in increased STAT3 and SOCS3. E+P maximally stimulated STAT3, whereas cAMP maximally stimulated SOCS3 during decidualization, suggesting E+P and cAMP differentially regulated the signaling components. IL-11 stimulated the phosphorylation (p) of STAT3 and SOCS3 mRNA and protein. Antiprogestin (onapristone) added to decidualizing cells attenuated STAT3 protein but increased SOCS3 mRNA and protein, suggesting regulation via both ligand-dependent and -independent progesterone-receptor pathways. SOCS3 overexpression in HESC reduced IL-11-induced pSTAT3 and retarded decidualization, indicating that SOCS3 is a critical regulator of differentiation. Immunoreactive pSTAT3 and SOCS3 were all present in decidualized stromal cells, epithelial cells, and leukocytes in human endometrium. These data support a role for IL-11 via pSTAT3 and SOCS3 in initiating and progressing decidualization.