Repeated estradiol administration alters different aspects of neurogenesis and cell death in the hippocampus of female, but not male, rats

Neuroscience. 2008 Apr 9;152(4):888-902. doi: 10.1016/j.neuroscience.2007.10.071. Epub 2008 Feb 8.


Estradiol has been shown to have neuroprotective effects, and acute estradiol treatment enhances hippocampal neurogenesis in the female brain. However, little is known about the effects of repeated administration of estradiol on the female brain, or about the effects of estradiol on the male brain. Gonadectomized male and female adult rats were injected with 5-bromo-2-deoxyuridine (BrdU) (200 mg/kg), and then 24 h later were given subcutaneous injections of either estradiol benzoate (33 mug/kg) or vehicle daily for 15 days. On day 16, animals were perfused and the brains processed to examine cells expressing Ki-67 (cell proliferation), BrdU (cell survival), doublecortin (young neuron production), pyknotic morphology (cell death), activated caspase-3 (apoptosis), and Fluoro-Jade B (degenerating neurons) in the dentate gyrus. In female rats, repeated administration of estradiol decreased the survival of new neurons (independent of any effects on initial cell proliferation), slightly increased cell proliferation, and decreased overall cell death in the dentate gyrus. In male rats, repeated administration of estradiol had no significant effect on neurogenesis or cell death. We therefore demonstrate a clear sex difference in the response to estradiol of hippocampal neurogenesis and apoptosis in adult rats, with adult females being more responsive to the effects of estradiol than males.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Bromodeoxyuridine / metabolism
  • Castration / methods
  • Cell Count
  • Cell Death / drug effects
  • Cell Proliferation / drug effects*
  • Doublecortin Domain Proteins
  • Doublecortin Protein
  • Enzyme-Linked Immunosorbent Assay / methods
  • Estradiol / administration & dosage
  • Estradiol / analogs & derivatives*
  • Estradiol / blood
  • Female
  • Hippocampus / cytology*
  • Hippocampus / drug effects*
  • Ki-67 Antigen / metabolism
  • Male
  • Membrane Proteins / metabolism
  • Microtubule-Associated Proteins / metabolism
  • Neurons / drug effects*
  • Neuropeptides / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sex Characteristics*


  • Dcx protein, rat
  • Doublecortin Domain Proteins
  • Doublecortin Protein
  • Ki-67 Antigen
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Neuropeptides
  • estradiol 3-benzoate
  • Estradiol
  • Bromodeoxyuridine