Progesterone metabolites rapidly stimulate calcium influx in human platelets by a src-dependent pathway

Steroids. 2008 Aug;73(7):738-50. doi: 10.1016/j.steroids.2008.02.008. Epub 2008 Feb 26.


The effects of several steroids and their metabolites were examined for their ability to rapidly alter intracellular free calcium ([Ca(2+)](i)) in the anucleate human platelet. Earlier studies suggested that steroids had direct and rapid non-genomic effects to alter platelet physiology. The rationale for performing this study was to investigate the signal transduction events being activated by steroids. Super-physiologic concentrations (1.0-10.0microM) of beta-estradiol and several estradiol metabolites and analogs potentiated (approximately twofold) the action of thrombin to elevate [Ca(2+)](i) in platelets, whereas 10.0microM progesterone inhibited the action of thrombin by 10-15%. Progesterone and beta-estradiol by themselves did not affect [Ca(2+)](i). Progesterone metabolites can achieve high blood concentrations. Some progesterone metabolites, particularly those in the beta-conformation, were potent stimulators of Ca(2+) influx and intracellular Ca(2+) mobilization in platelets. They activated phospholipase C because their ability to increase [Ca(2+)](i) was inhibited by the phospholipase C inhibitor U-73122. The ability of pregnanediol and collagen to increase [Ca(2+)](i) was inhibited by the src tyrosine kinase inhibitor PP1, whereas the actions of thrombin and thapsigargin to increase [Ca(2+)](i) were not affected by PP1. The effects of progesterone metabolites to increase [Ca(2+)](i) were observed with concentrations as low as 0.1microM. Pregnanolone synergized with thrombin to increase [Ca(2+)](i). It is hypothesized that human platelets possess receptors for progesterone metabolites. These receptors when stimulated will activate platelets by causing a rapid increase in [Ca(2+)](i). Pregnanolone, isopregnanediol and pregnanediol were the most effective stimulators of this newly identified src-dependent signal transduction system in platelets. Progesterone metabolites may regulate platelet aggregation and hence thrombosis in vivo.

MeSH terms

  • Blood Platelets / metabolism*
  • Calcium / metabolism*
  • Collagen / metabolism
  • Estradiol / metabolism*
  • Estradiol / pharmacology
  • Humans
  • Pregnanediol / metabolism
  • Progesterone / metabolism*
  • Progesterone / pharmacology
  • Signal Transduction
  • Steroids / pharmacology
  • Thrombin / metabolism*
  • Type C Phospholipases / metabolism
  • src-Family Kinases / metabolism


  • Steroids
  • Progesterone
  • Estradiol
  • Collagen
  • src-Family Kinases
  • Type C Phospholipases
  • Thrombin
  • Pregnanediol
  • Calcium