title: Estrous cycle and ovarian changes in a rat mammary carcinogenesis model after irradiation, tamoxifen chemoprevention, and aging.
abstract: OBJECTIVE
  Variation in the effects of selective estrogen receptor modulators (SERMs) on the estrous cycle and reproductive organs during aging could play an important role in the observed heterogeneity of tamoxifen chemoprevention efficacy against breast cancer.
  
  
  METHODS
  Of the 1,022 female Sprague Dawley rats enrolled in a long-term tamoxifen chemoprevention study, 87 were randomly chosen from four groups (irradiated, irradiated and tamoxifen treated, tamoxifen treated, and control). Vaginal smears were evaluated for determination of cycle stage, and vaginal pathologic changes. Correlation with the histologic features of reproductive tissues in 43 animals was made.
  
  
  RESULTS
  More tamoxifen-treated (21.9%; 7/32) rats had irregular cycling than did control (9%; 3/23) rats. Ovarian granulosa cell hyperplasia was present in 50% (3/6) of tamoxifen-treated rats, and 20% (2/10) of control rats. Endometrial-type cells (ETCs) were present only in tamoxifen-treated (tamoxifen alone 6.25% [2/32]) and tamoxifen/ radiation-treated (28.6% [4/14]) rats.
  
  
  CONCLUSIONS
  The modified Papanicolaou stain used here provided excellent morphologic detail for evaluating the estrous cycle in rodents. Tamoxifen altered vaginal cytologic and ovarian histologic features during aging. Results indicated that tamoxifen had direct and indirect effects on the reproductive tract, causing disturbance of the estrous cycle, shedding of ETCs, and promoting granulosa cell hyperplasia. Understanding of the heterogeneous response to tamoxifen chemoprevention during aging in rodents may provide important insights into the basis for tamoxifen chemoprevention failures in humans.
authors.affiliation: Department of Comparative Medicine, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, Maryland 21287, USA.
authors.forename: Baktiar O
authors.initials: BO
authors.lastname: Karim
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Landolfi
authors.forename: Archie
authors.initials: A
authors.lastname: Christian
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Ricart-Arbona
authors.forename: Weiping
authors.initials: W
authors.lastname: Qiu
authors.forename: Melissa
authors.initials: M
authors.lastname: McAlonis
authors.forename: Paul O
authors.initials: PO
authors.lastname: Eyabi
authors.forename: Khalid A
authors.initials: KA
authors.lastname: Khan
authors.forename: John F
authors.initials: JF
authors.lastname: Dicello
authors.forename: Jill F
authors.initials: JF
authors.lastname: Mann
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
mesh_terms: D000375:Aging; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D004195:Disease Models, Animal; D004343:Drug Implants; D030762:Estrous Cycle / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D010053:Ovary / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D065006:Papanicolaou Test; D018714:Radiotherapy, Adjuvant; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000627:therapeutic use; D013629:Tamoxifen / Q000008:administration & dosage / Q000627:therapeutic use*; D014621:Vagina / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D014626:Vaginal Smears
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004343:Drug Implants; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen