TGF-1 and TGF-3, but not TGF-2, are upregulated in the ovaries of ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) is a life-threatening and potentially fatal complication during in vitro fertilization treatment. The levels of transforming growth factor-beta 1 (TGF-beta 1) are upregulated in human follicular fluid and granulosa-lutein cells (hGL) of OHSS patients and could contribute to the development of OHSS by downregulating steroidogenic acute regulatory protein (StAR) expression. However, whether the same is true for the other two members of the TGF-beta family, TGF-beta 2 and -beta 3, remains unknown. We showed that all three TGF-beta isoforms were expressed in human follicular fluid. In comparison, TGF-beta 1 was expressed at the highest level, followed by TGF-beta 2 and TGF-beta 3. Compared to non-OHSS patients, follicular fluid levels of TGF-beta 1 and TGF-beta 3 were significantly upregulated in OHSS patients. The same results were observed in mRNA levels of TGF-beta isoforms in hGL cells and ovaries of OHSS rats. In addition, StAR mRNA levels were upregulated in hGL cells of OHSS patients and the ovaries of OHSS rats. Treatment cells with TGF-beta isoforms downregulated the StAR expression with a comparable effect. Moreover, activations of SMAD3 signaling were required for TGF-beta isoforms-induced downregulation of StAR expression. This study indicates that follicular fluid TGF-beta 1 and TGF-beta 3 levels could be used as biomarkers and therapeutic targets for the OHSS.