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Long-Term Progestin-Only Contraceptives Result in Reduced Endometrial Blood Flow and Oxidative Stress

School of Women’s and Infants’ Health (M.H.), University of Western Australia and Women and Infants Research Foundation, King Edward Memorial Hospital, Subiaco 6008, Western Australia; Department of Obstetrics, Gynecology and Reproductive Sciences (G.K., P.K., F.S., C.J.L.), School of Medicine, Yale University, New Haven, Connecticut 06520; and Department of Anatomy and Histology (C.C.), Flinders University of South Australia, Adelaide 5001, South Australia

Address all correspondence and requests for reprints to: Dr. Graciela Krikun, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, School of Medicine, 333 Cedar Street, New Haven, Connecticut, 06520-8063. E-mail: graciela.krikun{at}yale.edu.

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.

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