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


BACKGROUND
ClinicalTrials.gov NCT00346918.
Division of Nephrology, University Hospital, Zürich, Switzerland.
Matthias
M
Braun
James
J
Young
Cäcilia S
CS
Reiner
Diane
D
Poster
Fabienne
F
Krauer
Andreas D
AD
Kistler
Paulus
P
Kristanto
Xueqi
X
Wang
Yang
Y
Liu
Johannes
J
Loffing
Gustav
G
Andreisek
Arnold
A
von Eckardstein
Oliver
O
Senn
Rudolf P
RP
Wüthrich
Andreas L
AL
Serra
D000328:Adult; D000818:Animals; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D009839:Oligomenorrhea / Q000139:chemically induced* / Q000453:epidemiology; D010048:Ovarian Cysts / Q000139:chemically induced*; D006080:Ovarian Follicle / Q000187:drug effects; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy; D015995:Prevalence; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood
D007166:Immunosuppressive Agents; D020123:Sirolimus