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T. Suzuki, S.M. Richards, N.S. Treister, D.A. Sullivan; Antagonistic Effects of Testosterone and 17ß–Estradiol on Gene Expression in the Lacrimal and Meibomian Glands . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4427.
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Purpose: Researchers have discovered that androgens suppress and estrogens promote aqueous–deficient and/or evaporative dry eye syndromes. We hypothesize that these opposing sex steroid actions may involve antagonistic effects between androgens and estrogens on gene expression in the lacrimal and meibomian glands. The purpose of this study was to test our hypothesis. Methods: Lacrimal and meibomian glands were collected from young adult female, ovariectomized mice (n ≥ 5/treatment group; n = 3 separate experiments), that were treated with subcutaneous implants of estradiol–17ß (E2), testosterone (T) or vehicle for 2 weeks. Glands were pooled according to treatment, processed for the isolation of total RNA, and analyzed for differentially expressed mRNAs by using CodeLink Uniset Mouse I Bioarrays. Bioarray data were analyzed with bioinformatics and statistical programs made available through GeneSifter. Statistical significance (p < 0.05) was determined by using the Student’s t–test. Results: Our results demonstrate that E2 and T exert antagonistic effects on the expression of numerous genes in both the lacrimal and meibomian glands. In lacrimal tissue E2 significantly up–regulated the expression of 24 genes that were significantly down–regulated by testosterone (e.g. asialoglycoprotein receptor 1; mediates endocytosis of glycoconjugates and hepatitis C). Conversely, E2 suppressed the expression of 42 genes that were stimulated by T (e.g. dynamin binding protein; involved in endocytosis regulation). In the meibomian gland E2 increased, and T decreased, the level of only 1 gene transcript (i.e. cytochrome P450, family 2, subfamily g, polypeptide 1; a steroid hydroxylase). However, E2 significantly reduced the expression of 13 genes that were induced by T (e.g. matrix metalloproteinase 3; a proteoglycanase). Conclusions:These findings support our hypothesis that androgens and estrogens have antagonistic effects on gene expression in the lacrimal and meibomian glands. It is quite possible that that these opposing sex steroid actions may play a role in the pathogenesis of dry eye syndromes. (The authors thank Roderick V. Jensen for his help. This research was supported by grants from NIH [EY05612] and Allergan)
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