Low-Dose Oral Sirolimus and the Risk of Menstrual-Cycle Disturbances and Ovarian Cysts: Analysis of the Randomized Controlled SUISSE ADPKD Trial

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

Outcomes of everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex: A single institution experience in Japan

“…Irregular menstruation occurred at a high rate (65%, 15/23), and seven patients received hormone treatment to adjust menstruation. mTOR inhibitors decrease testosterone in males and progesterone in females, and irregular menstruation subsequently occurs in females . As many TSC‐AML patients are young, reduction of the gonadal function should be explained to patients before the initiation of everolimus treatment regardless of sex.…”

“…mTOR inhibitors decrease testosterone in males and progesterone in females, and irregular menstruation subsequently occurs in females. [20][21][22] As many TSC-AML patients are young, reduction of the gonadal function should be explained to patients before the initiation of everolimus treatment regardless of sex. ILD developed in 23% of the cases treated with everolimus for metastatic renal cell carcinoma, and the grade was 3 or higher in 30%, showing that ILD is a serious adverse event to which the closest attention should be paid.…”

The Role and Application of Sirtuins and mTOR Signaling in the Control of Ovarian Functions

“…The mTOR pathway plays a critical role in the regulation of ovarian cell proliferation, apoptosis, secretory activity, folliculogenesis, and malignant transformation [5,11,26,31,32,33,34,35,36,37,38,39,40,41,42,43,44]. The mTOR and SIRTs are in close mutual functional interrelationships.…”

“…These inhibitors were able to suppress porcine granulosa cells’ progesterone and testosterone output [26]. Furthermore, mTOR (like SIRTs) may mediate FSH action on ovarian cells; FSH affected mTOR in rat [38] and porcine [26] granulosa cells, while synthetic mTOR inhibitors prevented the stimulatory influence of FSH and induce the inhibitory effect of FSH on proliferation, apoptosis, and steroidogenesis in porcine granulosa cells [26]. Natural mTOR inhibitor (rapamycin) treatment promoted apoptosis in healthy porcine ovarian cells [13], suppressed follicular growth and maturation in rodents [19,32], and increased the risk of oligomenorrhea in humans [39].…”

Lymphangioleiomyomatosis: differential diagnosis and optimal management

“…More clinical trials are needed to ascertain optimal doses and treatment duration with sirolimus. The common adverse effects are oral ulcers, dyslipidemia, acneiform rash, irregular menses, etc 8,47. Patients are advised to stop sirolimus temporarily when pulmonary infections happen.…”