Successful reversal of ovarian hyperstimulation syndrome in a mouse model by rapamycin, an mTOR pathway inhibitor

Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening, iatrogenic complication of ovarian stimulation in assisted reproduction technology. This complex syndrome is characterised by enlarged ovaries with multiple corpora luteum, elevated sex steroid hormones in serum and increased capillary permeability. Until now, the pathogenesis of OHSS remains obscure, and no absolute strategy can fully prevent OHSS without any side effect on ovulation and clinical pregnancy. Using cultured human or mouse granulosa cells, our study revealed the time-dependent activation of the mTOR signaling pathway after human chorionic gonadotropin (hCG) treatment. The involvement of the mTOR signaling pathway was also observed in the development of OHSS in a mouse model. Selectively inhibiting mTOR signals by only two injections of rapamycin (2 mg/kg body weight), before or just after hCG treatment, significantly reduced vascular leakage and the severity of OHSS symptoms. Although ovarian angiogenesis was significantly inhibited, rapamycin could not decrease the elevated levels of vascular endothelial growth factor, IL-6 and IL-11 in OHSS ovaries. Further study showed the functional roles of the mTOR signaling pathway in the hyperstimulation-induced ovarian extracellular matrix remodeling as the expression of alpha 2M, a broad proteolytic inhibitor in both ovary and serum, was dramatically decreased after rapamycin treatment. Since a single injection of rapamycin during superovulation had no side effects on ovulation and early embryonic development, we propose rapamycin may be a good candidate to lower and prevent the risk of OHSS in the future.