Abstract
Sirolimus has been approved for clinical use in non proliferative and proliferative disorders. It inhibits the mammalian target of rapamycin (mTOR) signaling pathway which is also known to regulate ovarian morphology and function. Preliminary observational data suggest the potential for ovarian toxicity but this issue has not been studied in randomized controlled trials. We reviewed the self-reported occurrence of menstrual cycle disturbances and the appearance of ovarian cysts post hoc in an open label randomized controlled phase II trial conducted at the University Hospital Zürich between March 2006 and March 2010. Adult females with autosomal dominant polycystic kidney disease, an inherited kidney disease not known to affect ovarian morphology and function, were treated with 1.3 to 1.5 mg sirolimus per day for a median of 19 months (N = 21) or standard care (N = 18). Sirolimus increased the risk of both oligoamenorrhea (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.1 to 29) and ovarian cysts (HR 4.4, CI 1.1 to 26); one patient was cystectomized five months after starting treatment with sirolimus. We also studied mechanisms of sirolimus-associated ovarian toxicity in rats. Sirolimus amplified signaling in rat ovarian follicles through the pro-proliferative phosphatidylinositol 3-kinase pathway. Low dose oral sirolimus increases the risk of menstrual cycle disturbances and ovarian cysts and monitoring of sirolimus-associated ovarian toxicity is warranted and might guide clinical practice with mammalian target of rapamycin inhibitors.Trial RegistrationClinicalTrials.gov NCT00346918
Highlights
Sirolimus (Rapamune, Pfizer, New York, NY, USA) is a potent immunosuppressive and anti-proliferative drug which blocks the mammalian target of rapamycin
There were no reports of menstrual cycle disturbances and ovarian cyst formation in three large clinical trials [2,3,4], these adverse events were reported in three case series [5,6,7]
Ovarian cysts were recorded in 2 patients in the sirolimus group and in 4 patients in the control group (Table 2)
Summary
Sirolimus (Rapamune, Pfizer, New York, NY, USA) is a potent immunosuppressive and anti-proliferative drug which blocks the mammalian target of rapamycin (mTOR). MTOR is a key regulatory kinase which is known to regulate ovarian function [1]. Most of our knowledge regarding sirolimus toxicity has been derived from kidney transplant efficacy trials. There were no reports of menstrual cycle disturbances and ovarian cyst formation in three large clinical trials [2,3,4], these adverse events were reported in three case series [5,6,7]. Ovarian dysfunction is difficult to recognize in clinical trials: symptoms are often non-specific and can be wrongly attributed to concomitant medication or comorbidities [8]
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