Transforming growth factor (beta)1 in the human endometrium. Cyclic variation, increased expression by estradiol and progesterone, and regulation of plasminogen activators and plasminogen activator inhibitor-1

The purpose of this study was to identify cyclic variations and hormonal regulation of endometrial transforming growth factor (beta)1 (TGF(beta)1) mRNA. Regulation of the plasminogen-activating system was also examined, since it is involved in activation of latent TGF(beta)s. We measured TGF(beta)1 mRNA in 51 normal endometrial samples by Northern blot and densitometric scanning of autoradiograms. Each value was related to the corresponding (beta)-actin value to allow quantitative evaluation. TGF(beta)1 mRNA was higher in the mid and late secretory and menstrual phases than in the earlier parts of the cycle. This pattern implies progesterone dependence. The content of TGF(beta)1 mRNA in endometrial tissue explants obtained in the proliferative phase was significantly increased after stimulation for 4 days with estradiol + progesterone in vitro. Both TGF(beta)1 and estradiol + progesterone increased the content of plasminogen activator inhibitor-1 mRNA and protein in primary cultures of endometrial stromal cells. Conditioned- medium concentrations of urokinase plasminogen activator (u-PA) were increased by TGF(beta)1, but decreased by estradiol + progesterone. This effect of estradiol + progesterone results from increased internalization and degradation of u-PA secondary to up-regulation of the cell surface receptor for u-PA by progesterone (Casslen et al., JCEM 1995; 80: 2776-2784). Increased extracellular u-PA in response to TGF(beta)1 exposure was thus in concordance with an unchanged amount of available u-PA receptors on the cell surface. The activation mechanism of latent TGF(beta) involves u-PA activity; since u-PA activity is reduced in the secretory endometrium, we suggest that although TGF(beta)1 mRNA is increased in the mid and late secretory phase, TGF(beta)s are mainly in their latent form until the premenstrual rise in u-PA activity stimulates activation. TGF(beta) may promote capillary growth during endometrial regeneration.