High prevalence of ovarian cysts in premenopausal women receiving sirolimus and tacrolimus after clinical islet transplantation

Alfadhli, Eman; Koh, Angela; Albaker, Waleed; Bhargava, Ravi; Ackerman, Thomas; McDonald, Charlotte; Ryan, Edmond A.; Shapiro, A. M. James; Senior, Peter

doi:10.1111/j.1432-2277.2009.00839.x

Cited by 33 publications

(28 citation statements)

References 12 publications

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“…When sirolimus was discontinued, sperm parameters can improve. Sirolimus and FK association increased the frequency of ovarian cysts in premenopausal (70.5%) and postmenopausal (15.4%) women after islet transplant [121]. Sirolimus withdrawal was associated with a reduction in cyst size and resolution of cysts in 80% of subjects.…”

Section: Reproductive Abnormalities and Effects On Pregnancymentioning

confidence: 87%

The metabolic and toxicological considerations for immunosuppressive drugs used during pancreas transplantation

Rangel

2012

Expert Opinion on Drug Metabolism & Toxicology

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Immunosuppressive regimen after pancreas transplant is very effective and contributed to pancreas allograft survival. However, they present several side effects that are potentiated when drugs are combined. Modifiable and non-modifiable risk factors can aggravate metabolic and toxicological effects of immunosuppressive drugs. It is important to critically analyze the results of clinical studies and investigate new immunosuppressive drugs and/or novel drug combinations. It is equally important to comprehend and interpret experimental data. Therefore, minimization of side effects, based on safe approaches, can prolong pancreas allograft survival.

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Section: Reproductive Abnormalities and Effects On Pregnancymentioning

confidence: 87%

The metabolic and toxicological considerations for immunosuppressive drugs used during pancreas transplantation

Rangel

2012

Expert Opinion on Drug Metabolism & Toxicology

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“…The authors believed that the antiproliferative effect described by others [25,26] might interfere with the rupture of functional cysts, resulting in larger cysts. Again, FKBP65 in ovarian epithelium is a probable pathway for tacrolimus in normal ovary [10]. An inhibited tumor suppressor function through tacrolimus binding to FKBP65 might interfere with cellular proliferation and result in formation of ovarian cysts.…”

Section: Discussionmentioning

confidence: 97%

“…Generally, immunosuppressed patients run an increased risk to develop neoplasms. In premenopausal women undergoing pancreatic islet transplantation and having immunosuppression with tacrolimus, a high prevalence of ovarian cysts was described [10]. The authors believed that the antiproliferative effect described by others [25,26] might interfere with the rupture of functional cysts, resulting in larger cysts.…”

Section: Discussionmentioning

confidence: 97%

“…Olesen et al found an association between the expression of FKBP65 and colorectal cancer, where a monoclonal anti-human FKBP65 antibody did not stain normal colon mucosa while tumor cells of colorectal cancer showed strong expression [9]. Recently, women that were immunosuppressed after pancreatic islet transplantation revealed a high prevalence of ovarian cysts [10]. To reveal if FKBP65 is present in the ovary and in epithelial ovarian tumors and whether it might be of significance in ovarian pathology, we performed an immunohistochemical study of ovaries and ovarian tumors.…”

Section: Introductionmentioning

confidence: 95%

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Expression of FK506 binding protein 65 (FKBP65) is decreased in epithelial ovarian cancer cells compared to benign tumor cells and to ovarian epithelium

et al. 2011

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FK506 binding protein 65 (FKBP65) belongs to a group of proteins termed immunophilins that have a high binding affinity to immunosuppressant drugs as FK506 (tacrolimus) and rapamycin (sirolimus). Treatment of female premenopausal women with tacrolimus, which binds to FKBP65, has been reported to be followed by a strongly increased risk of ovarian cysts. We performed the present study to reveal how FKBP65 is expressed in the ovary and in ovarian tumors and to see if this expression might be related to ovarian tumor development, a relationship we have found in colorectal cancer. Biopsies from prospectively collected samples from ovaries and benign, borderline, and invasive ovarian tumors were analyzed for expression of FKBP65 by immunohistochemistry. The expression was compared to survival and several clinicopathological parameters. FKBP65 is strongly expressed in ovarian epithelium and in benign ovarian tumor cells. In the ovary, a positive staining was also found in endothelial cells of blood vessels. In non-invasive and in invasive malignant tumor cells, a decreased staining was observed, which was not correlated to stage, histology, or survival. A significant inversed correlation to expression of p53 was found. The differential expression of FKBP65 indicates a role in ovarian physiology as well as in ovarian tumor development. Our observations and the chromosomal localization of the FKBP65 gene indicate a tumor suppressor function of the FKBP65 protein in ovarian carcinogenesis.

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“…The hepatic steatosis may be due to the local secretion of insulin by islets in the liver although the significance of this remains unclear. Ovarian cysts and menstrual abnormalities were also described in female islet recipients, which seemed to be related to the use of sirolimus (20).…”

Section: Unusual Complicationsmentioning

confidence: 98%

Islet Transplantation at the University of Alberta: Status Update and Review of Progress over the Last Decade

Senior

Kin

Shapiro

et al. 2012

Canadian Journal of Diabetes

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Keywords: islet transplant type 1 diabetes hypoglycemia immunosuppressionMots clés: transplantation d'îlots diabète de type 1 hypoglycémie immunosuppression a b s t r a c tThe general perception of islet transplantation among the diabetes community is somewhat negative, as insulin independence was maintained in only a small minority and there are fears about the safety of lifelong immunosuppression. There has been substantial progress in refining the islet transplant procedure to enhance its safety, reduce the toxicity of immunosuppression and improve long-term graft function. Longer-term follow-up studies have clarified the indications for islet transplantation; frequent, severe hypoglycemia, hypoglycemia unawareness and glycemic lability; facilitated informed consent and provided a framework for more realistic expectations, and suggest beneficial effects on microvascular complications. One hundred thirty-eight individuals have undergone islet transplantation at the University of Alberta over the last 12 years. Of these, 109 (79%) have full or partial graft function. Patient survival is 96% with no deaths due to transplantation. Three subjects have been hospitalized because of severe opportunistic infection and 3 have progressed to require renal replacement therapy. Current protocols are able to achieve insulin independence rates of 60% beyond 4 years. Safer and more effective islet transplantation, along with refinements in immunosuppressive therapy, make islet transplantation a more attractive option for a subset of persons with type 1 diabetes who suffer from frequent, severe hypoglycemia, lability and/or hypoglycemia unawareness, and resulting in excellent glycemic control and freedom from hypoglycemia.Ó 2012 Canadian Diabetes Association r é s u m é L'opinion générale de la communauté diabétique sur la transplantation d'îlots est quelque peu négative, comme l'insulino-indépendance est maintenue par un petit nombre seulement et qu'il y a des craintes concernant l'innocuité de l'immunosuppression permanente. Des progrès considérables quant au raffinement de la technique de transplantation d'îlots ont eu pour effet d'améliorer son innocuité, de réduire la toxicité de l'immunosuppression et d'améliorer le fonctionnement du greffon à long terme. Les études de suivi à plus long terme ont précisé les indications de la transplantation d'îlots (hypoglycémie grave et fréquente, ignorance de l'hypoglycémie et instabilité glycémique), facilité le consentement informé et fourni un cadre pour des attentes plus réalistes, et elles laissent entrevoir des effets bénéfiques concernant les complications microvasculaires. Cent trente-huit individus (138) ont subi une transplantation d'îlots à l'Université de l'Alberta au cours des douze dernières années. Parmi eux, 109 (79 %) ont un fonctionnement du greffon complet ou partiel. La survie des patients est de 96 % sans décès attribués à la transplantation. Trois (3) sujets ont été hospitalisés en raison d'infection opportuniste grave et 3 ont évolué vers la thérapie de remplacem...

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High prevalence of ovarian cysts in premenopausal women receiving sirolimus and tacrolimus after clinical islet transplantation

Cited by 33 publications

References 12 publications

The metabolic and toxicological considerations for immunosuppressive drugs used during pancreas transplantation

The metabolic and toxicological considerations for immunosuppressive drugs used during pancreas transplantation

Expression of FK506 binding protein 65 (FKBP65) is decreased in epithelial ovarian cancer cells compared to benign tumor cells and to ovarian epithelium

Islet Transplantation at the University of Alberta: Status Update and Review of Progress over the Last Decade

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