Gonadal Steroids Regulate Proenkephalin Gene Expression in a Tissue-Specific Manner within the Female Reproductive System

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Abstract
Proenkephalin gene expression undergoes marked changes within the female reproductive system of rodents during the estrous cycle and in pregnancy. In order to define the factors responsible for this regulation, the effects of 17-.beta.-estradiol (E2) and progestrone (P4) have been examined in the ovary and uterus. In the ovary of the rat and hamster, E2 and P4 were without effect on proenkephalin RNA levels when injected individually. However, P4 increased ovarian transcript abundance 2- to 3-fold after pretreatment of animals with E2. In the uterus of either species, E2 had little effect but P4 alone stimulated both proenkephalin RNA abundance and total content severalfold. Glucocorticoids and androgen reproduced this stimulatory effect on proenkephalin transcipt levels. The interaction between E2 and P4 on proenkephalin geneexpression in the uterus varied with species. In the rat, E2 inhibited stimulation by P4, while in the hamster uterus the two hormones had a synergistic effect, producing a 15-fold elevation of proenkephalin RNA abundance and a 50-fold increase in total uterine content. These distinct steroid responses apppear to account for tissue- and species-related differences in the variation of proenkephalin gene expression during the estrous cycle in the rodent ovary and uterus. The stimulatory effect of P4 was shown to involve direct steroid action on the uterus and to be inhibited both by the steroid antagonist RU-486 and the transcriptional inhibitor actinomyicin D. These data are consistent with steroid receptor-mediated activation of proenkephalin gene transcription in uterine cells.