Long Term Progestin Only Contraception and Abnormal Uterine Bleeding.
Recent studies have focused on the effects of long term progestin only contraception (LTPOC) on aberrant angiogenesis. Although LTPOCs are highly effective and safe, irregular and prolonged endometrial breakthrough bleeding is the primary reason for discontinuing their use. Histological sections of endometria from LTPOC-treated patients display abnormally enlarged blood vessels at bleeding sites. Paradoxically, a trend towards reduced endometrial perfusion in LTPOC users has been reported in these patients. We hypothesized that hypoxia/re-perfusion-induced free radical production inhibits the expression of angiopoietin-1 (Ang-1), a vessel stabilizing factor, leaving unopposed the effects of endothelial Ang-2, a vessel branching and permeability factor. Immunohistochemical studies confirmed selective decreases in stromal cell Ang-1 in LTPOC-exposed endometrium. To indirectly assess whether LTPOC enhances endometrial free radical production, immunostaining was conducted for the phosphorylated form of the stress-activated kinases SAPK/JNK and p38. These kinases were greatly increased in endometria from LTPOC-treated patients. Hence, we are examining the effects of progestin, hypoxia and reactive oxygen species on the regulation of Ang-1 and 2 as well as the activation of MAPK, SAPK/JNK and p38 by cultured human endometrial stromal cells and human endometrial endothelial cells. The effect of these treatments on the production of lipid peroxides will also be conducted.
Understanding the mechanism of LTPOC induced endometrial bleeding is expected to lead to therapies that will alleviate or prevent this undesirable side effect.