A New Role for Activin in Endometrial Restoration Following Menses.

Knowledge of the molecular mechanisms underlying menstruation and menstrual disorders is limited. We propose that menstrual disorders are a result of incorrect or inadequate endometrial restoration/healing after menses, and that this is likely to be similar to a wound healing event. Wound healing occurs in three phases; inflammation, tissue formation and tissue remodelling. Similar events occur within the uterus during menstruation including a well characterised cascade of inflammatory responses. Thereafter rapid re-epithelialisation of the uterine surface occurs within the first 48h after the first two menstrual days followed closely by renewal of the stromal compartment. Activins are members of the transforming growth factor β (TGFβ) superfamily and include activin A. Follistatin, also a member of the TGFβ family binds activins with high affinity and inhibits their biological activity. In vivo studies support a contribution of endogenous activins to wound healing (ref). In βA over-expressing mice the rate of skin wound healing is enhanced, whilst in follistatin over-expressing mice wound healing is considerably delayed. We hypothesised that activin would enhance endometrial healing in vitro and in vivo. This study aimed to examine the contribution of activins to the healing process using both an in vitro wound healing assay, and our well characterised mouse model of endometrial breakdown and repair. The human endometrial epithelial cell line, ECC-1 was used for the in vitro assay. Cells were grown to confluence and wounded by vacuum suction. Cells were treated with carrier protein (bovine serum albumin) alone, activin A (50ng/ml) or EGF (positive control: 50ng/ml) and wound areas (expressed as % repair from original wound size) were quantitated for 6 days. For the in vivo study, mice over-expressing follistatin and wild-type (WT) littermates were subjected to a well characterised protocol to induce endometrial breakdown and repair to mimic menstruation in women (ref). Alterations in repair between the two groups were assessed using a morphological scoring system designed for our mouse model. ECC-1 wound repair was significantly (p3x those of WT littermates, only 50% of uterine sections assessed had completely repaired, compared to 85% of those from WT animals. Together these results provide functional evidence for a role for activin A in endometrial restoration following menses. This work further contributes to our understanding of the contribution of TGFβ superfamily members to endometrial biology, and provides new insights into possible treatment options for women suffering from menstrual disorders. Research supported by NHMRC of Australia (#388901) and an Australian Postgraduate Scholarship.