Menstrual disorders associated with sirolimus treatment

Introduction: Sirolimus has become a pillar in the treatment of vascular anomalies due to its inhibition of the mammalian target of rapamycin (mTOR). Adverse effects include metabolic and hematologic disorders among others, although menstrual disorders have not been well described.

Materials and methods: Retrospective review of patients with vascular anomalies on sirolimus treatment was performed. Patients presenting menstrual alterations were included.

Main results: One hundred and thirty-six patients with vascular anomalies on treatment with sirolimus were reviewed, finding seven women out of 74 (9.4%) who presented menstrual alterations attributable to the treatment. These seven patients presented with different vascular malformations and three showed pathogenic variants in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in affected tissue. Partial response in six and stability in one patient was obtained after treatment, administered for an average of 27.5 months (6-48). Five patients have completed treatment and two patients continue on after 12 and 15 months, respectively. All patients reported regular menstrual cycles prior to sirolimus treatment. One patient presented with amenorrhea for 4 months after treatment initiation that later spontaneously resolved. The other six patients presented with hypermenorrhea, four of them associating metrorrhagia. Most patients presented with mild menstrual alterations, without needing dose reduction or withdrawal, although one discontinued sirolimus due to hypermenorrhea, metrorrhagia, and hematuria. After sirolimus withdrawal, regular menstrual cycles were restored in five patients.

Conclusion: Sirolimus treatment can produce menstrual disorders as adverse effects. Although mild and reversible upon dose reduction or cessation of treatment, patients and physicians should be aware on this potential side effect.