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Die Wirkung von selektiven Östrogenrezeptor [alpha] und [beta]-Agonisten auf Ovar und Uterus am Nagetier

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Publikationsserver der RWTH Aachen University
Keywords
  • Info:Eu-Repo/Classification/Ddc/610
  • Medizin
  • Östrogenrezeptor Alpha
  • Östrogenrezeptor Beta
  • In Vivo
  • Proliferation
  • Follikulogenese
  • Apoptose
  • Progesteronrezeptor
  • Ratte
  • Maus
  • Hypophyse
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Abstract

Novel isotype selective estrogen receptor (ER) agonists, the selective ERAlphaagonist 16Alpha-LE2 and the selective ERBeta agonist 8Beta-VE2, were used in hypophysectomized rats or GnRH antagonist treated immature mice as well as in ovariectomized mature rats to elucidate the effect of subtype selective estrogens on the physiology of ovarian folliculogenesis, uterine proliferation and gene regulation, respectively. In immature hypophysectomized animals, the ERBeta agonist and the reference compound 17Beta-estradiol caused stimulation of early folliculogenesis, a decrease in follicular atresia and induction of ovarian gene expression. The ERBeta agonist exhibited the same efficiency and a similar high potency as 17Beta-estradiol in the respective studies. In contrast, the ERAlphaagonist had little or no effect on these parameters implying that direct estrogen effects on ovarian follicular development and gene regulation are mediated by ERBeta. In ovariectomized mature rats the ERAlpha agonist and the reference compound 17Beta-estradiol caused stimulation of uterine weight, cell proliferation and cell-compartment dependant gene regulation. The ERAlpha agonist exhibited the same efficiency and a similar high potency as 17Beta-estradiol in the respective studies. On the other hand, the ERBeta agonist did not stimulate uterine weight and cell proliferation in intact female rats and had no effect on gene regulation, showing that estrogen receptor Alpha is the dominant receptor in the uterus and responsible for mediating direct estrogen effects. This is in line with the assumption that stimulation of uterine growth and other known estrogen effects are mediated by ERAlpha but not by ERBeta and that ovarian ERBeta dominance is responsible for increased stimulation of folliculogenesis. This unique endocrine profile of selective estrogen receptor agonists provides new options for targeted pharmacotherapeutical indications as for example tailoring classical ovarian stimulation protocols by the use of ERBeta agonists or inventing new contraceptive agents by inhibition via an action on the hypothalamic-pituitary-ovarian axis by the use of ERAlpha agonists.

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