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Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):5153-8. doi: 10.1073/pnas.1424814112. Epub 2015 Apr 6.

Long-acting progestin-only contraceptives impair endometrial vasculature by inhibiting uterine vascular smooth muscle cell survival.

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Department of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612;
Department of Obstetrics & Gynecology, College of Medicine, The Ohio State University, Columbus, OH 43210;
Department of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612;
Department of Pediatric Endocrinology Research, School of Women's & Infants' Health, University of Western Australia, Crawley, WA 6009, Australia; and.
Department of Safety Pharmacology, Bayer HealthCare, GDD-GED-TOX-Safety Pharmacology, 42096 Wuppertal, Germany.


Molecular mechanisms responsible for abnormal endometrial vasculature in women receiving long-acting progestin-only contraceptives (LAPCs) are unknown. We hypothesize that LAPCs impair vascular smooth muscle cell (VSMC) and pericyte proliferation and migration producing thin-walled hyperdilated fragile microvessels prone to bleeding. Proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (αSMA) double-immunostaining assessed VSMC differentiation and proliferation in endometria from women before and after DepoProvera (Depo) treatment and from oophorectomized guinea pigs (OVX-GPs) treated with vehicle, estradiol (E2), medroxyprogesterone acetate (MPA), or E2+MPA. Whole-genome profiling, proliferation, and migration assays were performed on cultured VSMCs treated with MPA or etonogestrel (ETO). Endometrial vessels of Depo-administered women displayed reduced αSMA immunoreactivity and fewer PCNA (+) nuclei among αSMA (+) cells (P < 0.008). Microarray analysis of VSMCs identified several MPA- and ETO-altered transcripts regulated by STAT1 signaling (P < 2.22 × 10(-6)), including chemokine (C-C motif) ligand 2 (CCL2). Both MPA and ETO reduce VSMC proliferation and migration (P < 0.001). Recombinant CCL2 reversed this progestin-mediated inhibition, whereas a STAT1 inhibitor abolished the CCL2 effect. Similarly, the endometria of MPA treated OVX-GPs displayed decreased αSMA staining and fewer PCNA (+) nuclei in VSMC (P < 0.005). In conclusion, LAPCs promote abnormal endometrial vessel formation by inhibiting VSMC proliferation and migration.


VSMC; abnormal uterine bleeding; impaired vascular maturation; progestin contraceptives; proliferation

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