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

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


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.

Keywords: VSMC; abnormal uterine bleeding; impaired vascular maturation; progestin contraceptives; proliferation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Count
  • Cell Differentiation / drug effects
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chemokine CCL2 / metabolism
  • Contraceptive Agents, Female / pharmacology*
  • Desogestrel / administration & dosage
  • Desogestrel / pharmacology
  • Endometrium / blood supply*
  • Endometrium / pathology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Guinea Pigs
  • Humans
  • Medroxyprogesterone Acetate / administration & dosage
  • Medroxyprogesterone Acetate / pharmacology
  • Models, Biological
  • Muscle, Smooth, Vascular / pathology*
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / pathology*
  • Ovariectomy
  • Progestins / pharmacology*
  • Proliferating Cell Nuclear Antigen / metabolism
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects


  • Chemokine CCL2
  • Contraceptive Agents, Female
  • Progestins
  • Proliferating Cell Nuclear Antigen
  • STAT1 Transcription Factor
  • etonogestrel
  • Desogestrel
  • Medroxyprogesterone Acetate

Associated data

  • GEO/GSE55736