Estrous cycle and ovarian changes in a rat mammary carcinogenesis model after irradiation, tamoxifen chemoprevention, and aging.
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.
Karim
Baktiar O
BO
Department of Comparative Medicine, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, Maryland 21287, USA.
Landolfi
Jennifer A
JA
Christian
Archie
A
Ricart-Arbona
Rodolfo
R
Qiu
Weiping
W
McAlonis
Melissa
M
Eyabi
Paul O
PO
Khan
Khalid A
KA
Dicello
John F
JF
Mann
Jill F
JF
Huso
David L
DL
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
D018931:Antineoplastic Agents, Hormonal; D004343:Drug Implants; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen