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


METHODS
Endometrial perfusion was measured by laser-Doppler fluxmetry in women requesting LTPOCs. Endometrial biopsies were obtained for in vivo and in vitro experiments.


METHODS
The study was conducted in the Yale University School of Medicine and Family-Planning Center in Western Australia.


METHODS
Seven women 18 yr or older requesting implantable LTPOCs were recruited in Western Australia.


METHODS
Women received etonorgestrel implants.


RESULTS
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.
Hickey
M
M
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, School of Medicine, 333 Cedar Street, New Haven, Connecticut, 06520-8063, USA.
Krikun
G
G
Kodaman
P
P
Schatz
Frederick
F
Carati
C
C
Lockwood
C J
CJ
D000328:Adult; D001706:Biopsy; D003271:Contraceptive Agents, Female / Q000009:adverse effects / Q000494:pharmacology*; D017135:Desogestrel / Q000009:adverse effects / Q000494:pharmacology*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004717:Endometrium / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017078:Laser-Doppler Flowmetry; D018384:Oxidative Stress / Q000187:drug effects*; D045167:Progesterone Congeners / Q000009:adverse effects / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014592:Uterine Hemorrhage / Q000139:chemically induced
D003271:Contraceptive Agents, Female; D045167:Progesterone Congeners; C075750:8-epi-prostaglandin F2alpha; C044815:etonogestrel; C002744:3-nitrotyrosine; D014443:Tyrosine; D017135:Desogestrel; D015237:Dinoprost