Sidelining a Side Effect of Long-Acting Contraceptives

Long-acting injections or implants based on synthetic progesterone are highly effective as contraceptives. But a common side effect—abnormal uterine bleeding—reduces adherence to this method. A new study suggests that this bleeding occurs because of abnormalities in the vascular smooth muscle cells that surround arteries and veins [1]. Previous studies have shown that women receiving longacting progestin-only contraceptives have abnormal endometrial blood vessels; these blood vessels have thin walls and are excessively dilated. Umit Kayisli et al. took a closer look at such blood vessels in women treated with the injectable contraceptive Depo-Provera. Depo-Provera reduced the proliferation of vascular smooth muscle cells, as measured by a marker of cell division. Similar results were obtained in guinea pigs treated with Depo-Provera. The researchers next turned to cell-based experiments using vascular smooth muscle cells derived from the human female aorta—such cells express the progesterone receptor. They showed that either Depo-Provera or Implanon, which is used as an implant, could slow proliferation of these cells, as well as inhibit their migration in cell-based migration assays. Micorarray analysis identified hundreds of genes with altered transcription in response to these contraceptives—one gene down-regulated by both treatments encodes CCL2 (chemokine [C-C motif ligand 2]). CCL2 is known to promote proliferation of vascular smooth muscle cells through the transcription factor STAT1. Similarly, administering CCL2 could overcome the proliferation defect imposed by DepoProvera or Implanon, an effect that seemed to be mediated by STAT1. These findings open the door to in vivo experiments asking if administering CCL2 with long-acting contraceptives might rescue blood vessel defects and prevent bleeding.