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Regulation of Uterine 5-Reductase Type 1 in Mice¹

^a Department of Obstetrics and Gynecology, Divisions of Reproductive Endocrinology and Urogynecology, University of Texas Southwestern Medical Center, Dallas, Texas 75390

ABSTRACT

A null mutation in the murine gene encoding steroid 5-reductase type 1 (5R1) leads to failure of normal parturition at term. This observation, together with the finding that mRNA levels of uterine 5R1 increase significantly at term in normal pregnant animals, indicates that 5R1 plays an important role in murine parturition. The current studies were conducted to elucidate the regulation of 5R1 in uterine tissues of nonpregnant and pregnant animals. Nonpregnant, ovariectomized ICR mice were treated with vehicle (control), 17ß-estradiol (E₂), progesterone (P₄ ), or E₂+P₄ for 3 days. Thereafter, uterine tissues were obtained for histology, quantification of 5R1 specific activity, and Northern blot analysis of 5R1 mRNA expression. The 5R1 enzyme activity was significantly increased in animals treated with E₂+P₄. However, activity was much less in uterine tissues from E₂+P₄-treated animals than in uterine tissues from pregnant animals near term. To evaluate further the regulation of 5R1 during gestation, mice underwent unilateral tubal ligation before timed matings. The 5R1 activity increased eightfold in uterine tissues from the fetal horn from Gestational Days 12 to 18. This temporal pattern in 5R1 activity paralleled marked increases in uterine diameter. Taken together, these studies indicate that expression of 5R1 is regulated by E₂+P₄ in uterine tissues. Whereas E₂ alone is insufficient to induce enzyme activity, E₂ may be required to increase P₄ receptors and, thereby, mediate the effects of P₄ on 5R1 gene expression. Further increases in enzyme activity during late gestation are mediated by fetal occupancy, possibly through stretch-induced increases in endometrial growth. Thus, like other genes involved in parturition, expression of 5R1 is regulated by both hormonal and fetal-derived signaling pathways.

FOOTNOTES

First decision: 10 January 2001.

¹ Supported by NIH P01-11149. D.M. was supported by the Ortho McNeil ACOG-Ortho Academic Training Fellowship in Obstetrics and Gynecology and NRSA 5-T32-HD07190.

² Correspondence: R. Ann Word, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9032. FAX: 214 648 8066; ruth.word{at}utsouthwestern.edu

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