Published online before print July 19, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.060979

Accepted for publication May 31, 2007.

Article

Delay of Postnatal Maturation Sensitizes the Mouse Prostate to Testosterone-Induced Pronounced Hyperplasia. Protective Role of Estrogen Receptor-

Saija Savolainen^*, Tomi Pakarainen, Ilpo Huhtaniemi, Matti Poutanen, and Sari Mäkelä^*@

From the Functional Foods Forum,* the Department of Physiology, Institute of Biomedicine, and the Department of Biochemistry and Food Chemistry, University of Turku, Turku, Finland; and the Institute of Reproductive and Developmental Biology, Imperial College, London, United Kingdom

^@ To whom correspondence should be addressed. E-mail: sarmak{at}utu.fi.

	Abstract

The role of estrogens in the etiology of prostate cancer is controversial. To demonstrate the specific effects of estrogens and androgens on the development of the prostatic epithelial hyperplasia, we used luteinizing hormone receptor knockout mice (LuRKO), which are resistant to pituitary regulation mediated by luteinizing hormone, lack postnatal androgen production, and have rudimentary accessory sex glands, the growth of which can be induced with exogenous androgen replacement. This model is thus ideal for the investigation of direct hormonal effects on the prostate. Testosterone, but not 5-dihydrotestosterone, replacement from 21 days of life for 8 weeks induced pronounced hyperplasia and inflammation in the prostates of LuRKO mice. Interestingly, 5-dihydrotestosterone combined with 17-estradiol did not induce hyperplasia or inflammation, and treatments with inhibitors of estrogen action, aromatase inhibitor, and ICI 182780 further exacerbated testosterone-induced hyperplastic growth. However, the activation of estrogen receptor (ER)- with a specific agonist, DPN [2,3-bis(4-hydroxyphenol)-propionitrile], prevented the development of prostatic hyperplasia and inflammation in testosterone-treated LuRKO mice. Thus, it seems that in the presence of sufficient androgenic stimulation, it is the balance between ER-- and ER--mediated signaling that determines whether estrogens promote hyperplasia or protect the prostate against hyperplastic changes.