TGF1 is thought to be intimately involved in cyclic tissue remodelling and inflammatory events associated with menstruation. Menstruation is initiated by progesterone withdrawal; however the underlying mechanisms are not well understood. In the present study, we have tested the hypothesis that locally produced TGF1 may influence expression of progesterone receptor (PR), or the Wnt antagonist, Dickkopf-1 (DKK) with consequential impact on regulation of menstruation.

Endometrial stromal cells (ESC) were isolated from endometrial biopsy samples collected from patients undergoing gynaecological procedures for benign indications. Treatment of differentiated ESC with TGF1 (10 ng/ml) significantly inhibited the expression of mRNAs encoding PR and DKK. TGF1 also attenuated the protein expression of PR and secretion of DKK proteins in culture supernatants. Neutralization of endogenous TGF1 signaling abolished the TGF1-induced effects, significantly increased expression of PR, and increased DKK protein release levels to that of differentiated ESCs, confirming the specificity of the TGF1 effect. Additionally, in vitro decidualization of ESCs, significantly augmented DKK protein release. Moreover, although TGF1 was capable of signaling via the SMAD pathway, the inhibitory effect on DKK was SMAD independent. Conversely, the inhibitory effects of TGF1 on PR was dependent on SMAD signal transduction.

In conclusion, these results suggest that local TGF1 signaling can potentiate progesterone withdrawal by suppressing expression of PR and may coordinate tissue remodeling associated with menstruation by inducing Wnt-signaling via inhibition of DKK, which we found to be upregulated as a consequence of decidualization of ESCs.