Effects of Norplant on endometrial tissue factor expression and blood vessel structure

Abnormal uterine bleeding after Norplant administration is primarily respon sible for the high discontinuation rate of this safe and effective long-act ing implantable progestin-only contraceptive agent. Although tissue factor (TF) is the primary initiator of hemostasis, previous studies indicated tha t Norplant-associated bleeding persists despite relatively high TF levels i n the stromal compartment. Recently, we determined that progestin-enhanced TF expression during decidualization of human endometrial stromal cells inv olves both the epidermal growth factor receptor and progesterone receptor ( PR). The current study evaluated TF levels in endometrial bleeding (BL) and nonbleeding (NBL) sites obtained by camera-guided hysteroscopy during Norp lant contraception. After 1 yr of therapy, immunohistochemical TF levels we re unexpectedly higher at BL than at NBL sites. Use of immunohistochemistry and Western blotting indicated that both sites displayed elevated epiderma l growth factor receptor levels and that the BL sites exhibited high levels of the PR, as well as the PR,and the PR, isoforms. Microscopic examination of 1-yr biopsies revealed that significantly larger numbers of enlarged, d istended vessels were present in BL, compared with NBL sites. Elevated TF l evels and abnormally enlarged blood vessels in the BL sites are consistent with the recently discovered angiogenic role of TF. By promoting aberrant a ngiogenesis, chronic endometrial overexpression of TF could produce fragile vessels, which are at increased risk to bleed. Analysis of endometrial BL and NBL sites, during Norplant contraception, offers the potential of eluci dating local mechanisms that control enhanced TF expression, leading to abn ormal angiogenesis at specific endometrial sites.