The Effect of Levonorgestrel on Fibrinolytic Factors in Human Endometrial Endothelial Cells

Reprod Sci. 2016 Nov;23(11):1536-1541. doi: 10.1177/1933719116645193. Epub 2016 Apr 28.


Objective: The levonorgestrel-releasing intrauterine system is considered a highly effective treatment of heavy menstrual bleeding (HMB). While LNG has established effects on the stromal and glandular compartments of the endometrial tissue, its effect on the endometrial endothelial cells has not been investigated. We examined whether LNG regulates fibrinolytic factors, tissue plasminogen activator (tPA), and urokinase plasminogen activator (uPA) secreted by human endometrial endothelial cells (HEECs) and determined the steroid receptor through which LNG exerts its effect on the endothelium.

Methods: The HEECs were treated with LNG or progesterone and levels of tPA and plasminogen activator inhibitor 1 (PAI-1) measured. The HEECs were specifically examined for the presence of androgen receptors through Western blot. Levonorgestrel ± flutamide were added to HEECs and the levels of tPA and uPA were examined.

Results: An enzyme-linked immunosorbent assay performed on culture media confirmed a statistically significant decrease in tPA levels in cells treated with LNG (77.80% ± 8.0% of control; n = 5, P < .05 vs control) but not progesterone. The androgen receptor (110 kDa) was detected in HEEC lysates. The decrease in tPA was blocked by the addition of flutamide (101.3% ± 16% of control), a classic nonsteroidal androgen receptor blocker. There was no change in uPA or PAI-1 levels in cells treated with LNG.

Conclusions: Levonorgestrel decreases tPA levels through the androgen receptor in HEECs. Thus, LNG inhibits tPA secretion by the endometrial endothelial cell. This response suggests reduction in HMB with LNG-IUS could reflect an LNG-mediated promotion of hemostasis.

Keywords: endothelial cells; heavy menstrual bleeding; levonorgestrel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Endometrium / drug effects*
  • Endometrium / metabolism
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Female
  • Flutamide / administration & dosage
  • Humans
  • Levonorgestrel / administration & dosage*
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • Progesterone / administration & dosage
  • Receptors, Androgen / metabolism*
  • Tissue Plasminogen Activator / metabolism*
  • Urokinase-Type Plasminogen Activator / metabolism*


  • AR protein, human
  • Plasminogen Activator Inhibitor 1
  • Receptors, Androgen
  • SERPINE1 protein, human
  • Progesterone
  • Levonorgestrel
  • Flutamide
  • Tissue Plasminogen Activator
  • Urokinase-Type Plasminogen Activator