Summary: Complete androgen-insensitivity syndrome (CAIS), a disorder of sex development (46,XY DSD), is caused primarily by mutations in the androgen receptor (AR). Gonadectomy is recommended due to the increased risk of gonadoblastoma, however, surgical intervention is often followed by loss of libido. We present a 26-year-old patient with CAIS who underwent gonadectomy followed by a significant decrease in libido, which was improved with testosterone treatment but not with estradiol. Genetic testing was performed and followed by molecular characterization. We found that this patient carried a previously unidentified start loss mutation in the androgen receptor. This variant resulted in an N-terminal truncated protein with an intact DNA binding domain and was confirmed to be loss-of-function in vitro. This unique CAIS case and detailed functional studies raise intriguing questions regarding the relative roles of testosterone and estrogen in libido, and in particular, the potential non-genomic actions of androgens.
Learning points: N-terminal truncation of androgen receptor can cause androgen-insensitivity syndrome. Surgical removal of testosterone-producing gonads can result in loss of libido. Libido may be improved with testosterone treatment but not with estradiol in some forms of CAIS. A previously unreported AR mutation - p.Glu2_Met190del (c.2T>C) - is found in a CAIS patient and results in blunted AR transcriptional activity under testosterone treatment.