Transforming growth factor β1 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.