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Coordinate Regulation of the Production and Signaling of Retinoic Acid by Estrogen in the Human Endometrium

Department of Integrative Biology and Pharmacology (L.D., G.L.S., D.S.L.-M., G.M.S., P.J.A.D.), University of Texas Houston Health Science Center, Houston, Texas 77030; Department of Pathology (R.B.), University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; and Wyeth Research (J.H.P.), Philadelphia, Pennsylvania 19087

Address all correspondence and requests for reprints to: Dr. Peter J. A. Davies, University of Texas Houston Health Science Center, Department of Integrative Biology and Pharmacology, MSB 5.104, 6431 Fannin Street, Houston, Texas 77030. E-mail: peter.j.davies{at}uth.tmc.edu.

To determine whether estrogen regulates retinoic acid (RA) production and signaling in the human endometrium as it does in the rodent uterus, we investigated the effects of estrogens on the expression of RA-metabolizing enzymes, retinoid receptors, and biomarker genes in the post- and premenopausal human endometrium. Real-time quantitative PCR revealed that retinaldehyde dehydrogenase (RALDH) 2, a critical enzyme in RA biosynthesis, was induced 4-fold by estrogen replacement therapy with either Premarin or a mixture of estrone and equilin sulfates for 3 months. Estrogen replacement therapy also increased the expression of the RA receptor RAR 1.9-fold. In parallel, there was a marked increase in the expression of two RA-regulated genes, cellular retinoic acid-binding protein II and tissue transglutaminase. In the premenopausal endometrium, the levels of RALDH1, RALDH2, RAR, and cellular retinoic acid-binding protein II were increased in the estrogen-dominated proliferative phase, and the transcripts for the RA catabolic enzyme retinoic acid 4-hydroxylase (CYP26A1) and tissue transglutaminase were significantly increased in the secretory phase. Our results suggest that estrogen coordinately up-regulates RA production and signaling in the human endometrium. This coordinate mechanism may play a role in the antiproliferative effects that counterbalance the estrogen-induced endometrial proliferation.

Abbreviations: CRABP2, Cellular retinoic acid binding protein II; CYP26A1, retinoic acid 4-hydroxylase; EES, estrone and equilin sulfate; ERT, estrogen replacement therapy; PMSG, pregnant mare serum gonadotropin; QRT-PCR, quantitative RT-PCR; RA, retinoic acid; RALDH, retinaldehyde dehydrogenase; RAR, retinoic acid receptor; tTG, tissue transglutaminase.

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