sirolimus and Ovarian-Cysts

Ovarian cysts are a common finding in reproductive-aged females. Most of them are functional cysts that typically resolve spontaneously and require no treatment. However, ovarian cysts may also be adverse events associated with inhibitors of the mammalian target of rapamycin (mTOR). Both approved mTOR inhibitors everolimus and sirolimus are widely used as immunosuppressive agents after organ transplantation. The aim of this study was to compare the effect of mTOR inhibitors vs. non-mTOR inhibitor immunosuppression on the incidence, size and complication rate of ovarian cysts in renal transplant recipients.. We retrospectively analysed 571 consecutive female kidney transplant patients in our centre between 2000 and 2008. The follow-up period was extended through December 31st, 2012.. 102 (17.8%) patients received mTOR inhibitors for at least one month after transplantation. We identified 44 women (7.7%) with new ovarian cysts. Ovarian cysts were significantly more frequent among patients receiving mTOR inhibitors (20.5%) than in the control group (4.9%; p < 0.001). Also the hospitalization rate was higher (p = 0.05) in the mTOR group and ten patients (47.6%) requiring surgery.. Future prospective studies are required to determine the underlying cause of ovarian toxicity and treatment strategies have to be developed in order to avoid severe complications.

Topics: Adolescent; Adult; Child; Everolimus; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Middle Aged; Ovarian Cysts; Postoperative Complications; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases; Transplant Recipients; Treatment Outcome; Young Adult

Topics: Adult; Female; Humans; Immunosuppressive Agents; Menstrual Cycle; Ovarian Cysts; Ovary; Polycystic Kidney, Autosomal Dominant; Sirolimus

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.. ClinicalTrials.gov NCT00346918.

Topics: Adult; Animals; Female; Humans; Immunosuppressive Agents; Oligomenorrhea; Ovarian Cysts; Ovarian Follicle; Polycystic Kidney, Autosomal Dominant; Prevalence; Rats; Rats, Wistar; Sirolimus

We encountered an unexpectedly high rate of ovarian cysts in premenopausal women receiving sirolimus and tacrolimus following islet transplantation. The goal of this retrospective chart review was to determine the frequency of ovarian cysts found on pelvic ultrasound examinations of female islet transplant recipients and to look for potential causal factors. Fifty-seven women with a median age of 42.5 years underwent islet transplantation at the University of Alberta. Ovarian cysts were found in 31 out of 44 (70.5%) premenopausal and two out of 13 (15.4%) postmenopausal women (P = 0.001). No women using combined oral contraception developed ovarian cysts. Eight women required surgery; in four women undergoing cystectomy or unilateral oophorectomy, ovarian cysts recurred. Sirolimus withdrawal was associated with a reduction in cyst size and resolution of cysts in 80% of subjects. The risk of ovarian cysts should be discussed with female islet transplant candidates and pelvic ultrasounds performed routinely post-transplant.

Topics: Abdomen; Adult; Canada; Diabetes Mellitus, Type 1; Female; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Middle Aged; Ovarian Cysts; Postmenopause; Premenopause; Prevalence; Retrospective Studies; Risk Factors; Sirolimus; Tacrolimus; Treatment Outcome; Ultrasonography