title: An evolutionary test of the isoform switching hypothesis of functional progesterone withdrawal for parturition: humans have a weaker repressive effect of PR-A than mice.
abstract: BACKGROUND
  A decrease in maternal serum progesterone (P4) concentrations precedes the onset of labor in most placental mammals. Humans differ by maintaining high levels of P4 throughout birth. Parturition in humans probably includes mechanisms that undercut the pregnancy sustaining function of P4. One attractive hypothesis is the isoform switching hypothesis (ISH). ISH is supported by in vitro evidence that progesterone receptor isoform A (PR-A) inhibits PR-B and that the PR-A/PR-B ratio increases towards term.
  
  
  METHODS
  Here, we test the hypothesis that isoform switching is an adaptation to high levels of P4 at term, predicting that, in humans, PR-A mediated repression of PR-B is stronger than in mouse. We use reporter assays with human and mouse PRs to detect species differences in the repressive effects of PR-A.
  
  
  RESULTS
  We found that human PR-B is less sensitive to repression by human PR-A than mouse PR-B, contrary to our prediction. The difference between human and mouse PR-B sensitivity is most pronounced at PR-A/PR-B ratios typical for the preterm myometrium.
  
  
  CONCLUSIONS
  Our results are inconsistent with the ISH. We speculate that, instead, the lower sensitivity of human PR-B to PR-A may be relevant for the maintenance of pregnancy at high progesterone levels and increasing PR-A concentrations towards term.
authors: Yale Systems Biology Institute and Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA. gunter.wagner@yale.edu
authors: Günter P
authors: GP
authors: Wagner
authors: Yingchun
authors: Y
authors: Tong
authors: Deena
authors: D
authors: Emera
authors: Roberto
authors: R
authors: Romero
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D051379:Mice; D009215:Myometrium / Q000737:chemistry; D036801:Parturition / Q000097:blood / Q000502:physiology*; D011247:Pregnancy; D011255:Pregnancy Maintenance / Q000502:physiology; D011374:Progesterone / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology; D011980:Receptors, Progesterone / Q000032:analysis / Q000502:physiology*; D013045:Species Specificity
chemical_list: D020033:Protein Isoforms; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D011374:Progesterone