Sirolimus‐Associated Infertility: Case Report and Literature Review of Possible Mechanisms

Deutsch, Marcus-André; Kaczmarek, Ingo; Huber, Stephan; Schmauß, Daniel; Beiras-Fernández, Andrés; Schmoeckel, Michael; Ochsenkuehn, Robert; Meiser, Bruno; Mueller-Hoecker, Josef; Reichart, Bruno

doi:10.1111/j.1600-6143.2007.01929.x

Cited by 71 publications

(56 citation statements)

References 29 publications

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“…It is not clear if this high prevalence is population-related, owing to ethnic and genetic predisposition, or if there is lack of reporting of this complication in the international literature. The metabolic and proteinuric complications of sirolimus seen in our patients are in line with the findings in the literature [14]. However, our observation that serum creatinine improved after sirolimus discontinuation suggests a nephrotoxic effect of sirolimius, contrary to what has been previously reported.…”

Section: Discussionsupporting

confidence: 64%

“…On the other hand, the first case report of sirolimus-related infertility in a male renal transplant patient was reported by Bererhi et al in 2003 [11]. One case of oligospermia in a male heart-lung transplant patient and another case of azoospermia in a male renal transplant were reported [14,15]. The prevalence as well as the clinical impact of sirolimus-related gonadal suppression was not documented in the above-mentioned studies.…”

Section: Discussionmentioning

confidence: 84%

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Gonadal dysfunction and infertility in kidney transplant patients receiving sirolimus

et al. 2009

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Sirolimus is an immunosupressor of the mammalian target of rapamycin inhibitors (mTOR-I) group. Recent studies have emphasized a potential impact of sirolimus on male gonadal function. We report our clinical experience with sirolimus-induced gonadal dysfunction and infertility in both male and female kidney transplant patients. Of the 170 kidney transplant patients, nine (5.3%) patients (six males and three females) were receiving sirolimus. Follow-up data for two male patients were not available. The one unmarried female patient developed amenorrhea post-transplantation and had resumption of her menstrual cycles after discontinuation of sirolimus. The remaining six married patients (four males and two females), who all had fathered or conceived children in the pre-transplantation period, developed gonadal dysfunction and infertility on average 5-12 months after transplantation. Sirolimus was discontinued in all four male patients with full recovery of the oligo/azospermia and restoration of fertility. Both married female patients developed amenorrhea post-transplantation. Sirolimus was discontinued in one female patient with resumption of her menstrual cycles. In this small population of patients treated with sirolimus, the prevalence rate of reversible gonadal dysfunction and infertility was significant in both males and females. Infertility secondary to sirolimus is under-diagnosed and should be studied further.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 84%

Gonadal dysfunction and infertility in kidney transplant patients receiving sirolimus

et al. 2009

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“…Following kidney transplant, women treated with long-term sirolimus (13 mo or longer) developed amenorrhea, which resolved with its discontinuation, and men who were azoospermic developed normal semen parameters and fathered children following discontinuation (46). Case reports describe temporary azoospermia in men treated with sirolimus, which resolved after its discontinuation or switch to a different agent, and a rodent study further demonstrated the reversible impact of sirolimus on male fertility (47,48).…”

Section: Discussionmentioning

confidence: 99%

mTORC1/2 Inhibition Preserves Ovarian Function and Fertility During Genotoxic Chemotherapy

Goldman

Chenette

Arju

et al. 2017

Obstetrical &Amp; Gynecological Survey

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The ovary contains oocytes within immature (primordial) follicles that are fixed in number at birth. Activation of follicles within this fixed pool causes an irreversible decline in reproductive capacity, known as the ovarian reserve, until menopause. Premenopausal women undergoing commonly used genotoxic (DNA-damaging) chemotherapy experience an accelerated loss of the ovarian reserve, leading to subfertility and infertility. Therefore, there is considerable interest but little effective progress in preserving ovarian function during chemotherapy. Here we show that blocking the kinase mammalian/mechanistic target of rapamycin (mTOR) with clinically available small-molecule inhibitors preserves ovarian function and fertility during chemotherapy. Using a clinically relevant mouse model of chemotherapy-induced gonadotoxicity by cyclophosphamide, and inhibition of mTOR complex 1 (mTORC1) with the clinically approved drug everolimus (RAD001) or inhibition of mTORC1/2 with the experimental drug INK128, we show that mTOR inhibition preserves the ovarian reserve, primordial follicle counts, serum anti-Mullerian hormone levels (a rigorous measure of the ovarian reserve), and fertility. Chemotherapy-treated animals had significantly fewer offspring compared with all other treatment groups, whereas cotreatment with mTOR inhibitors preserved normal fertility. Inhibition of mTORC1 or mTORC1/2 within ovaries was achieved during chemotherapy cotreatment, concomitant with preservation of primordial follicle counts. Importantly, our findings indicate that as little as a two-to fourfold reduction in mTOR activity preserves ovarian function and normal birth numbers. As everolimus is approved for tamoxifen-resistant or relapsing estrogen receptor-positive breast cancer, these findings represent a potentially effective and readily accessible pharmacologic approach to fertility preservation during conventional chemotherapy. mTOR | fertility | chemotherapy | ovary | ovarian function

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“…In general, men have normal testosterone after transplant (200), but sirolimus, in particular, has been reported to reduce sperm count and in some cases alter gonadotropins, as well as reduce fertility rates (202,203). It is currently unknown whether a male transplant recipient on immunosuppression can confer any other risk to a child that is conceived.…”

Section: Eye Care Foot Care Preventing Infections and Reproductmentioning

confidence: 99%

Post-Transplant Diabetes Mellitus: Causes, Treatment, and Impact on Outcomes

Shivaswamy

Boerner

Larsen³

2015

Endocrine Reviews

239

203

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and VA Nebraska-Western Iowa Health Care System (V.S.), Omaha, Nebraska 68105Post-transplant diabetes mellitus (PTDM) is a frequent consequence of solid organ transplantation. PTDM has been associated with greater mortality and increased infections in different transplant groups using different diagnostic criteria. An international consensus panel recommended a consistent set of guidelines in 2003 based on American Diabetes Association glucose criteria but did not exclude the immediate post-transplant hospitalization when many patients receive large doses of corticosteroids. Greater glucose monitoring during all hospitalizations has revealed significant glucose intolerance in the majority of recipients immediately after transplant. As a result, the international consensus panel reviewed its earlier guidelines and recommended delaying screening and diagnosis of PTDM until the recipient is on stable doses of immunosuppression after discharge from initial transplant hospitalization. The group cautioned that whereas hemoglobin A1C has been adopted as a diagnostic criterion by many, it is not reliable as the sole diabetes screening method during the first year after transplant. Risk factors for PTDM include many of the immunosuppressant medications themselves as well as those for type 2 diabetes. The provider managing diabetes and associated dyslipidemia and hypertension after transplant must be careful of the greater risk for drug-drug interactions and infections with immunosuppressant medications. Treatment goals and therapies must consider the greater risk for fluctuating and reduced kidney function, which can cause hypoglycemia. Research is actively focused on strategies to prevent PTDM, but until strategies are found, it is imperative that immunosuppression regimens are chosen based on their evidence to prolong graft survival, not to avoid PTDM. (Endocrine Reviews 37: 37-61, 2016)

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Sirolimus‐Associated Infertility: Case Report and Literature Review of Possible Mechanisms

Cited by 71 publications

References 29 publications

Gonadal dysfunction and infertility in kidney transplant patients receiving sirolimus

Gonadal dysfunction and infertility in kidney transplant patients receiving sirolimus

mTORC1/2 Inhibition Preserves Ovarian Function and Fertility During Genotoxic Chemotherapy

Post-Transplant Diabetes Mellitus: Causes, Treatment, and Impact on Outcomes

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