Abstract
ObjectivesTo determine the impact of everolimus on female fertility, including menstrual irregularities, secondary amenorrhea, and luteinizing and follicle stimulating hormone levels in female patients.DesignA pooled analysis from 3 prospective studies consisting of a core phase (≥6 months) and a long-term follow-up open-label extension.SettingOne phase 2 single-center and two phase 3 multicenter studies.ParticipantsData were obtained from female participants, restricted to those between 10 and 55 years of age, during 1 of 3 of the described clinical trials of everolimus. Patients had received ≥ 1 dose of everolimus.Main outcome measuresIncidence of fertility events.ResultsA total of 43/112 patients (38.4%) experienced at least 1 menstrual irregularity. The most common events were amenorrhea (24.1%) and irregular menstruation (17.0%). Seven patients (6.3%) experienced grade 3/4 amenorrhea. When only the longest duration period of amenorrhea for each patient was considered, the median duration was 291 days. Fifteen patients attained menarche during the treatment period in any of the pooled studies. The mean age of menarche for this group was 12.4 years, similar to that of patients who were postmenarche at study entry (12.2 years). A total of 19/92 patients (20.7%) who were postmenarche at baseline or during the study experienced an irregular menstruation event. An increased luteinizing hormone level was reported as an adverse event in 3/112 patients (3%), and follicle-stimulating hormone levels were within normal limits for these patients.ConclusionsNo new safety concerns emerged regarding endocrine function and menstruation in female patients with tuberous sclerosis complex–associated subependymal giant cell astrocytoma or angiomyolipoma, who were receiving everolimus.Trial registrationClinicalTrials.gov NCT00411619, NCT00789828, NCT00790400
Highlights
Tuberous sclerosis complex (TSC) is a multisystemic, autosomal dominant genetic disorder that occurs in approximately 1:6000 births [1] and affects up to 1 million people globally [2]
NCT00789828 (EXIST-1 Phase 3 Study) Á Franz DN, Belousova E, Sparagana S, et al Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial
Á Kingswood JC, Jozwiak S, Belousova ED, et al The effect of everolimus on renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, placebo-controlled, Phase 3 trial EXIST-1
Summary
Tuberous sclerosis complex (TSC) is a multisystemic, autosomal dominant genetic disorder that occurs in approximately 1:6000 births [1] and affects up to 1 million people globally [2]. This disorder is a result of mutations in the TSC1 or TSC2 genes, responsible for producing protein complexes that act on the mammalian target of rapamycin (mTOR) complex, mTORC1 [3,4,5,6,7,8]. It has been approved in pediatric and adult patients with TSC who have SEGAs that require therapeutic intervention but cannot be curatively resected [14]
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