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VASCERN-VASCA Consensus Statement: Sirolimus and Fertility 

This document is based on the statement elaborated by ASPHO SIG (The American Society of Pediatric Hematology/Oncology Special Interest Group) and CaNVAS (Consortium of iNvestigators of Vascular AnomalieS), USA in December 2023, and further revised by the VASCERN (European Reference Network for Multisystemic Rare Vascular Diseases) VASCA (Vascular Anomalies) working group.  

VASCERN-VASCA Consensus Statement: Sirolimus and Fertility  

Recent concerns have been raised about the impact of sirolimus (rapamycin) treatment on fertility in both men and women with vascular anomalies. The VASCERN-VASCA consensus statement brought international specialists in Vascular Anomalies together to address this issue by examining the current knowledge.  

Sirolimus has been approved by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approval for use in both organ transplant and for treatment of Lymphangioleiomyomatosis (LAM). This means extensive studies addressing the efficacy and safety of sirolimus have been completed outside of vascular anomalies. However, it is important to recognize the similarities and differences between these populations. 

In contrast to individuals with vascular anomalies treated with sirolimus, organ transplant patients: 

  1. are treated with different immunosuppressive therapies in addition to sirolimus; 
  2. sirolimus is given for life following organ transplant; 
  3. daily doses of sirolimus are generally higher; and 
  4. often experience a period of sustained and progressive organ failure and are treated with multiple therapies prior to transplant.  

LAM is a rare multisystem neoplastic disease that is characterized by cystic lung destruction, angiomyolipoma, and lymphangioleiomyomas that affect women. Sirolimus is an effective treatment for LAM and is generally given for years at doses similar to those used to treat vascular anomalies. 

A summary of the current literature on the effects of sirolimus treatment on gonadal function is detailed below:  

  1.  Sirolimus effects on gonadal function are reversible: 

    In 2012, rat studies indicated that sirolimus reduced testosterone levels and blocked spermatogenesis, with complete recovery upon treatment withdrawal. In 2013, a publication summarized the impact of sirolimus on fertility, based on different case reports that suggested a reversible impact of sirolimus on fertility and pregnancy in male and female solid organ transplant patients. These case reports described patients who experienced decreased sperm number and function while taking sirolimus, as well as lower sex hormone levels, with normalization of these dysfunctions when sirolimus was discontinued. A report of one heart transplant patient on sirolimus noted a poor in vitro fertilization outcome, which improved with discontinuation of the drug.  

     

  2. Women may experience menstrual cycle disturbances and ovarian cysts with sirolimus. 

    Women may experience menstrual cycle problems and development of ovarian cysts while taking sirolimus.  These symptoms improve with the reduction of the sirolimus dose or after stopping the medication.  In a recent report from the European multicentric phase III trial VASE (vascular anomaly-sirolimus -Europe), the incidence of dysmenorrhea (pain with menstruation) was low (10%), and all were mild. Dysmenorrhea resolved when sirolimus was stopped.  

     

  3. Pregnancy is possible after sirolimus use Numerous reports highlight successful pregnancies in solid organ transplant patients and those with Lymphangioleiomyomatosis (LAM) on long-term sirolimus therapy.

    Preliminary results from the European multicentric phase III trial VASE showed that pregnancy is highly and rapidly feasible during the follow up period after being treated for two years with sirolimus: Four pregnancies occurred (including one fathered pregnancy) in three patients. 

FDA and EMA Statements on Sirolimus

Based on various observations, the European Medicines Agency (EMA) stated in the summary of product characteristics (Smpc) for sirolimus: Impairments of sperm parameters have been observed among some patients treated with Sirolimus. These effects have been reversible upon discontinuation of Sirolimus in most cases. 

In the United States the Food and Drug Administration (FDA) stated: Azoospermia has been reported with the use of sirolimus and has been reversible upon discontinuation of sirolimus in most cases.   

Future Directions  

Although the studies surrounding fertility and gonadal function for patients with vascular anomalies are few (but increasing), it is still very important for vascular anomaly experts to be aware of data from other disease states and understand the current gaps in knowledge.  More clinical studies are needed to better understand gonadal function in vascular anomaly patients and how medical treatments, including sirolimus and newer targeted therapies, can affect this function.  

Conclusion 

The current evidence suggests that the effects of sirolimus on gonadal function are generally mild and reversible. Vascular anomaly experts should stay informed of new findings, sharing these with their patients so they can make informed decisions about treatment and its effects on their reproductive health. 

See the consensus statement.

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