SAT-288 Successful Virilization of a PAIS Patient with a Missense Mutation In The Ligand-binding Domain Of The Androgen Receptor with Combined High-dose Testosterone and Aromatase Inhibitor

Abstract

The main complain of patients with partial androgen insensitivity patients (PAIS) is undervirilization signs and the small penile length. Supplemental androgen therapy has enhanced virilization in only a few patients with PAIS. Aromatase inhibitors as anastrozole and letrozole are nonsteroidal inhibitors able to bind reversibly to the heme group of cytochrome P450 reducing estrogen and estrone levels and increasing LH and FSH levels and consequently testosterone levels. We hypothesized that the combination of high-dose testosterone with anastrozole can maintain a sustained elevated testosterone levels and also deviated testosterone metabolization from estrogen to DHT, therefore increasing penile length. Case Report This experimental treatment was proposed and both patient and parents willing to participate. Patient was firstly evaluated at 7 yrs of age. The hemizygous c.2599G>C; p.V867L AR in the ligand-binding domain (LBD) was found in both affected siblings. He was previously submitted to three unsuccessful genital masculinizing surgeries and bilateral orchidopexia. The external genitalia presented a microphalus (penile length of 2 cm, -4.5 SDS), perineal hypospadias and bilateral topic testis. He received testosterone cypionate (50 mg IM injections monthly, for 3 times at age of 7 and 200 mg IM injections monthly, for 4 times at age of 8); topic DHT gel (5-10 g/daily for three months at age of 7 yrs). At age of 12.3 yrs, the genital masculinization surgeries were completed, penile length was 3.5 cm (-2.6 SDS), testicular size of 2.6x1.5 cm and pubic hair Tanner II stage. LH and FSH levels were (9.4 and 3.2 IU/L respectively), testosterone (304 ng/dL), DHT (26 ng/dL) and estradiol (<17 pg/mL). The effect of 200 mg of testosterone cypionate weekly associated to 1 mg of anastrozole daily was evaluated. After 6 months of treatment, he presented enlargement of penile length (7.0 cm, -1 SDS), and testicular size (3.0x2.0 cm) and Tanner IV of pubic hair. Gynecomastia was absent. The hormonal profile showed: decreased values of LH and FSH (0.8 and 1.1 IU/L respectively), and estradiol (<17 pg/mL) levels, and increased testosterone and DHT levels (1753 and 167 ng/dL, respectively). Bone age did not advance during treatment. Conclusion This is the first documentation of successful virilization in a PAIS boy with androgen insensitivity due to a hemizygous missense mutation in AR with a combination of high-dose testosterone and aromatase inhibitor.