Steroid-modulated stromal cell tissue factor expression: a model for the regulation of endometrial hemostasis and menstruation.

Abstract

This study examined steroidal regulation of tissue factor expression by cultured endometrial stromal cells. Confluent stromal cell cultures derived from cycling human endometria were exposed to vehicle control, 10(-8) mol/L estradiol (E2), 10(-8)-10(-6) mol/L medroxyprogesterone acetate (MPA), or both E2 and MPA for 2-24 days in serum-containing medium. The progestin enhanced immunoreactive and functionally active stromal cell tissue factor content, achieving peak effects by 8-12 days of culture. Although E2 alone was ineffective, it augmented MPA-enhanced tissue factor content by 8 days of culture, with continued increases beyond 20 days. Dose-dependent effects on tissue factor protein content were observed between 10(-8)-10(-6) mol/L MPA added alone or together with E2. The content of tissue factor mRNA was also increased by MPA and synergistically increased by E2 plus MPA. Similar steroidal effects on stromal cell tissue factor protein and mRNA content were observed using a defined medium. After optimal induction of tissue factor expression by E2 plus MPA, removal of these steroids reduced levels of stromal cell tissue factor mRNA and protein, with virtually complete reversal by day 7 of withdrawal. These time-course and dose-response relationships establish in vitro conditions with which to dissect factors controlling endometrial hemostasis, whereas the observed effects of steroid withdrawal establish a novel model for the study of mechanisms regulating normal and abnormal uterine bleeding.

Inflammatory pathways in female reproductive health and disease

“…TF is the primary initiator of haemostasis generating fibrin and leading to clot formation ( Fig. 1; Lockwood et al 1993). Fibrinolysis leading to clot degradation is regulated by the availability of plasmin by the action of PA. Progesterone increases TF expression but decreases PA expression, therefore progesterone withdrawal immediately prior to menstruation induces a haemorrhagic environment with decreased clotting and increased fibrinolysis (Casslen et al 1995).…”

The Immunoconjugate “Icon” Targets Aberrantly Expressed Endothelial Tissue Factor Causing Regression of Endometriosis

“…30,39 -41 We have also shown that glandular epithelial cells display minimal TF expression throughout the menstrual cycle. 30,39,40 The present study sought to determine the pattern and extent of TF expression in endometriosis and observed anomalous endothelial expression of TF in ectopic versus eutopic endometrium. This expression likely reflects the strong association of endometriosis with increased inflammatory cytokine production.…”

Interferon-γ Modulates Prolactin and Tissue Factor Expression in Differentiating Human Endometrial Stromal Cells1

“…TF is a 262-amino acid membrane-bound glycopeptide whose expression in ES cells, in vivo and in vitro, mimics that of decidual PRL (13,16,17). Serum factors are known to induce TF expression in several cell types, including ES cells, and consequently confluent cultures were maintained in low serum (2% DCC-FBS) for 48 h before treatment with cAMP, IFN␥, or their combination.…”

“…In human endometrium, TF expression has been reported to be closely associated with decidual transformation and is often used as a biochemical marker of this differentiation process (13,16,17). The distinct temporal and spatial expression of TF in the endometrium indicates a pivotal role in maintaining vascular integrity before menstruation and, if pregnancy occurs, during intravascular trophoblast invasion (16,17). We previously reported that TF expression in primary cultures mimics that of PRL, characterized by rapid induction in response to cAMP treatment, which is further enhanced by the addition of progestins.…”

“…Primary culture of human ES cells induced to express PRL and tissue factor (TF), two well established end points of decidualization (12)(13)(14)(15)(16)(17), were therefore investigated for the inhibitory activity of IFN␥. We provide evidence that IFN␥ is a potent inhibitor of decidual PRL expression, but these effects do not extent to TF.…”