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Mol. Hum. Reprod. Advance Access published online on February 18, 2009
Molecular Human Reproduction, doi:10.1093/molehr/gap013
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© The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Overexpression of progesterone receptor A-isoform (PR-A) in mice leads to endometrial hyperproliferation, hyperplasia and atypia

M.C. Fleisch1,2, Y.C. Chou1, Robert D. Cardiff3, A. Asaithambi1 and G. Shyamala1

1Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA 94720 2Current address: Dep. of Obstetrics and Gynecology, Heinrich-Heine-University, D-40255 Düsseldorf, Germany 3Center for Comparative Medicine, University of California at Davis, Davis, CA 95616

Corresponding Author: Markus C. Fleisch, MD Department of Obstetrics and Gynecology Heinrich-Heine-University Moorenstr. 5 D-40225 Düsseldorf Germany Fleisch{at}uni-duesseldorf.de Tel.: +49 211 8117500 Fax.: +49 211 8118384

A delicate balance in estrogen and progesterone signaling through their cognate receptors is characteristic for the physiologic state of the endometrium and a shift in receptor isotype expression can be frequently found in human endometrial pathology. In this study, using a transgenic mouse model, we examined the mechanisims whereby alterations in progesterone receptor isotype expression leads to endometrial pathology.

For an experimental model we used transgenic mice (PR-A transgenics) carrying an imbalance in the native ratio of the two progesterone receptor isoforms A and B through expression of additional A form, and examined their uterine phenotype under different hormonal regimens, using various criteria.

Uterine epithelial cell proliferation was augmented in PR-A transgenics and was abolished by PR antagonists. In particular, proliferative response to progesterone, independent of signaling through estrogen, was enhanced. Upon continuous exposure to estradiol and progesterone, the uteri in PR-A transgenics displayed gross enlargement, endometrial hyperplasia including atypical lesions, endometritis and pelvic inflammatory disease.

Imbalanced expression of the two isoforms of PR in a transgenic model reveals multiple derangements in the regulation of uterine physiology resulting in various pathologies including hyperplasias.

Key Words: Progesterone receptor/isotype/inflammation/hyperplasia/atypia

Submitted on June 17, 2008; resubmitted on February 13, 2009; accepted on February 14, 2009.


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