Long-term progestin-only contraceptives result in reduced endometrial blood flow and oxidative stress

CONTEXT: Because of their safety and efficacy, long-term progestin-only contraceptives (LTPOCs) are well-suited for women with restricted access to health care. However, abnormal uterine bleeding (AUB) causes half of all users to discontinue therapy within 12 months. Endometria of LTPOC-treated patients display aberrant angiogenesis with abnormally enlarged, thin-walled, fragile blood vessels, inflammation, and focal hemorrhage. In this study, similar effects were observed with a new third-generation implantable LTPOC. OBJECTIVE: We hypothesized that LTPOC reduces uterine and endometrial blood flow, leading to hypoxia/reperfusion, which triggers the generation of reactive oxygen species. The latter induce aberrant angiogenesis, causing AUB. DESIGN: Endometrial perfusion was measured by laser-Doppler fluxmetry in women requesting LTPOCs. Endometrial biopsies were obtained for in vivo and in vitro experiments. SETTING: The study was conducted in the Yale University School of Medicine and Family-Planning Center in Western Australia. Patients: Seven women 18 yr or older requesting implantable LTPOCs were recruited in Western Australia. INTERVENTION: Women received etonorgestrel implants. MAIN OUTCOME: LTPOC treatment resulted in reduced endometrial perfusion and increased endometrial oxidative damage. CONCLUSIONS: We propose that LTPOCs result in hypoxia reperfusion, which leads to aberrant angiogenesis resulting in AUB.