Activin A Is a Functional Component of the Anti-Endometriotic Drug Endoferin

Endometriosis is a prevalent gynecological condition affecting up to 25-40% of women with infertility. Endoferin, a protein complex derived from the bovine ovarian follicles, has demonstrated high efficacy in clinical trials for treating endometriosis. It contains bovine serum albumin and a biologically active protein from the TGF-β superfamily. However, the mechanisms underlying its therapeutic effects are not studied well. Immunoblotting revealed that TGF-β in Endoferin is presented by predominantly pro-activin A (56 kDa) and to lesser extend by mature activin A (32 kDa). Heating endoferin facilitated the processing of pro-activin A to activin A, enhancing its differentiation-inducing activity in Xenopus ectoderm. Protease assays and inhibitor studies indicated that MMP-9 is responsible for this processing. Immunohistochemical analysis showed that endoferin treatment significantly decreased VEGF expression by 42% to 83% compared to control (p < 0.05) and increased apoptosis indices up to 4.5-fold (p < 0.05) in rat endometriotic tissue samples. The therapeutic efficacy of endoferin in treating endometriosis is attributed to the ability of activin A to suppress angiogenesis and induce apoptosis in a surgical model of the endometriosis in rats and activate apoptosis in endometriomas. MMP-9-mediated processing of pro-activin A is crucial for activating activin A within the preparation. These findings support the use of endoferin as a promising non-hormonal treatment option for endometriosis.