title: Letrozole increases ovarian growth and Cyp17a1 gene expression in the rat ovary.
abstract: OBJECTIVE
  To evaluate the effects of letrozole on ovarian size and steroidogenesis in vivo, as well as on proliferation and steroidogenesis of theca-interstitial cells alone and in coculture with granulosa cells using an in vitro model.
  
  
  METHODS
  In vivo and in vitro studies.
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  Immature Sprague-Dawley female rats.
  
  
  METHODS
  In vivo effects of letrozole were studied in intact rats receiving either letrozole (90-day continuous-release SC pellets, 400 μg/d) or placebo pellets (control group). In in vitro experiments, theca cells were cultured alone or in coculture with granulosa cells in the absence or presence of letrozole.
  
  
  METHODS
  Deoxyribonucleic acid synthesis was determined by thymidine incorporation assay; steroidogenesis by mass spectrometry; and steroidogenic enzyme messenger RNA (mRNA) expression by polymerase chain reaction.
  
  
  RESULTS
  In vivo, letrozole induced an increase in ovarian size compared with the control group and also induced a profound increase of androgen, LH levels, and Cyp17a1 mRNA expression. Conversely, a decrease in Star, Cyp11a1, and Hsd3b1 transcripts was observed in letrozole-exposed rats. In vitro, letrozole did not alter either theca cell proliferation or Cyp17a1 mRNA expression. Similarly, letrozole did not affect Cyp17a1 transcripts in granulosa-theca cocultures.
  
  
  CONCLUSIONS
  These findings suggest that letrozole exerts potent, but indirect, effect on growth of rat ovary and dramatically increases androgen levels and Cyp17a1 mRNA expression, the key enzyme regulating the androgen biosynthesis pathway. The present findings reveal novel mechanisms of action of letrozole in the rat ovary.
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, University of California, Davis, California, IVI-Madrid, Madrid, Spain.
authors.forename: Israel
authors.initials: I
authors.lastname: Ortega
authors.forename: Anna
authors.initials: A
authors.lastname: Sokalska
authors.forename: Jesus A
authors.initials: JA
authors.lastname: Villanueva
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Cress
authors.forename: Donna H
authors.initials: DH
authors.lastname: Wong
authors.forename: Elisabet
authors.initials: E
authors.lastname: Stener-Victorin
authors.forename: Scott D
authors.initials: SD
authors.lastname: Stanley
authors.forename: Antoni J
authors.initials: AJ
authors.lastname: Duleba
mesh_terms: D000818:Animals; D047072:Aromatase Inhibitors / Q000494:pharmacology; D001426:Bacterial Proteins; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006107:Granulosa Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006728:Hormones / Q000378:metabolism; D000077289:Letrozole; D009570:Nitriles / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D010053:Ovary / Q000187:drug effects* / Q000254:growth & development* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*; D013799:Theca Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D047072:Aromatase Inhibitors; D001426:Bacterial Proteins; D006728:Hormones; D009570:Nitriles; D012333:RNA, Messenger; D012097:Repressor Proteins; C120883:SprA protein, Salmonella typhimurium; D014230:Triazoles; D000077289:Letrozole; C582555:CYP17A1 protein, rat; D013254:Steroid 17-alpha-Hydroxylase