Endocrine Abstracts

JOINT1007

Apalutamide is a selective antagonist of the androgen receptor, increasingly used in the treatment of prostate cancer. In the SPARTAN and TITAN trials, an increased risk of subclinical or severe hypothyroidism was reported, much higher in patients treated with levothyroxine prior to apalutamide than in untreated patients. Apalutamide is suggested to cause hypothyroidism by inducing UDP-glucuronosyltransferase activity leading to reduced exposure to levothyroxine, but other mechanisms can be considered in patients treated with levothyroxine. A 65-year-old man underwent total thyroidectomy for Graves’ disease followed by 150 μg/day levothyroxine supplementation with normal TSH level (3.9 mU/l). Eight months later, apalutamide (240 mg/day) associated with triptorelin (GnRH agonist intramuscular injections every 3 months) treatment was started for his metastatic prostate cancer. After one month of apalutamide treatment, follow-up of the patient revealed increased TSH (47.9 mU/l) level, and the dosage of levothyroxine was gradually increased to normalize TSH level. In this patient treated with levothyroxine (275 μg/day, 3.25 μg/kg/day) and refractory hypothyroidism (TSH = 38 mU/l, Free T4 = 7.9 pg/ml), a levothyroxine absorption test was performed: after a fast overnight, the patient intake orally 1000 μg levothyroxine, blood samples were drawn for TT4 determinations at baseline and then every 2 hours during 24 hours. Percentage absorption of levothyroxine was calculated using the formula: increment TT4 (μg/dl) × 10 × 0.442 × BMI × 100/total administered levothyroxine. After 1000 μg levothyroxine intake, TT4 presented a rise from 5.8 μg/dl at baseline toward peak level at 2 hours (8.1 μg/dl) with percentage of absorption at 27.1% (normal > 60%) demonstrating significantly reduced T4 absorption. Then TT4 declined at 5.7 μg/dl after 16 hours followed with a TT4 rise toward second peak level at 20 h (8.5 μg/dl): increased UDP-glucuronosyltransferase activity with T4 enterohepatic circulation and secondarily intestine T4 absorption likely explaining this second peak of T4 concentration. No adverse events were observed during the test. In conclusion, apalutamide treatment worsened hypothyroidism via decreased levothyroxine absorption and increased T4 clearance in this patient, explaining the higher prevalence of refractory hypothyroidism in levothyroxine-treated patients during apalutamide treatment.