Low-dose oral sirolimus and the risk of menstrual-cycle disturbances and ovarian cysts: analysis of the randomized controlled SUISSE ADPKD trial

Matthias Braun, James Young, Cäcilia S Reiner, Diane Poster, Fabienne Krauer, Andreas D Kistler, Paulus Kristanto, Xueqi Wang, Yang Liu, Johannes Loffing, Gustav Andreisek, Arnold von Eckardstein, Oliver Senn, Rudolf P Wüthrich, Andreas L Serra, Matthias Braun, James Young, Cäcilia S Reiner, Diane Poster, Fabienne Krauer, Andreas D Kistler, Paulus Kristanto, Xueqi Wang, Yang Liu, Johannes Loffing, Gustav Andreisek, Arnold von Eckardstein, Oliver Senn, Rudolf P Wüthrich, Andreas L Serra

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 registration: ClinicalTrials.gov NCT00346918.

Conflict of interest statement

Competing Interests: ALS received consulting fees from Hoffmann–La Roche and Nycomed, and grant support from Wyeth (now Pfizer); DP received travel support from Wyeth (now Pfizer); ADK received lecture fees from Wyeth and Genzyme, and travel support from Amgen; JY is an employee of Biometrical Practice BIOP; PK is an employee of Aardex; RPW received consulting and lecture fees from Genzyme, Novartis and Wyeth, and grant support from Wyeth. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Enrollment and Outcomes.
Figure 1. Enrollment and Outcomes.
Figure 2. Oligoamenorrhea (upper panel) and the…
Figure 2. Oligoamenorrhea (upper panel) and the size (lower panel; in millimeters) and the left-right location (R, L) of ovarian cysts over time in the sirolimus (orange) and control (blue) groups.
Figure 3. Time course of adherence parameters…
Figure 3. Time course of adherence parameters (persistence and adherence) in patients assigned to the sirolimus group.
The persistence curve shows a Kaplan Meier estimation of the proportion of patients on treatment. The adherence curve indicates the day-to-day proportion of patients who took sirolimus as prescribed. Data from 21 individual dosing histories were used for this analysis.
Figure 4. Molecular (Panel A and B)…
Figure 4. Molecular (Panel A and B) and imunohistochemical analyses (Panel C) of rat ovary.
Panel A. Gel electrophoresis of proteins carried out to assess sirolimus-associated changes in the activity of key signaling pathways thought to regulate ovarian function and morphology. Sirolimus treatment amplified signaling through phosphatidylinositol 3-kinase (AktSer743), thought to be associated with human polycystic ovarian syndrome, and blocked the mammalian target of rapamycin pathway (p70 S6KThr421). Panel B. The ratios of phosphorylated to non-phosphorylated molecules are expressed in arbitrary densitometric units (Sirolimus minus control – mean (95% confidence interval): p70 S6KThr421/Ser424 to p70 S6K −0.28 (−0.57 to 0.02) and AktSer473 to Akt 0.34 (0.09 to 0.59). Panel C: Immunohistochemical analysis shows positive staining with a nuclear pattern for AktSer743 in granulosa cells of rats receiving sirolimus and for p70 S6KThr421 in granulosa cells of control rats receiving vehicle.

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