Endocrine Abstracts

Context: Androgen insensitivity syndrome (AIS) is a rare X-linked recessive disordercaused by mutations in the androgen receptor (AR) gene resulting in variable target tissue resistance to androgen action. The underlying molecular defect causes a spectrum of androgen dysfunction ranging from gynecomastia and/or infertility in mild AIS (MAIS) to variable degrees of ambiguous or undermasculinized genitalia in partial AIS to complete testicular feminization in complete AIS. To date, more than 800 different mutations in theAR gene have been identified.

Objective: We report a previously undescribed mutation in the AR gene associated with MAIS in two adult patients, one presenting for infertility and the other for a decrease in athletic performance. We characterize the functional impact of this mutation using 3D modeling studies.

Patients: Patient 1 was referred at the age of 38 years for infertility. He had gynecomastia and normal external genitaliaexcept for mild hypospadias. His semen analysis showed oligoasthenoteratospermia. Lab results revealed high testosterone levels, an elevated FSH, and an elevated androgen sensitivity index (ASI) suggesting AIS. The couple underwent successful in vitro fertilization and intracytoplasmic sperm injection resulting in a twin pregnancy. Patient 2 was referred at the age of 45 years for evaluation of a fatigue and a decrease in physical athletic performance. He had a history of gynecomastia, surgically treated during adolescencebut normal external genitalia. He alsopresented with oligoasthenoteratospermia, hightestosterone plasma levels and an elevated ASI. Despite his impairedsemen analysis, he fathered two children without assisted reproductive technology. Because of his persistent fatigue, the patient was offered a trial of high dose dihydrotestosterone therapy which improved his symptoms and his quality of life. Family history for infertility or gynecomastia was negative in both patients.

Results and conclusions: Sequence analysis of AR gene in the two patients revealed a common previously undescribed missense mutation, Ala699Thr, within the ligand binding domain. Structural analysis showed that this mutation may impact dimer stability upon ligand binding or may affect allosteric changes upon dimerization. This study highlights the usefulness of structural studies in providing a greater understanding of the functional consequences of a mutation and expands the databaseof AR gene mutations. The proper diagnosis of adult patients with MAIS may be helpful for the adequate counseling of infertile male patient undergoing assisted reproductive techniques. In addition, a trial of high dose androgen therapy may improve symptoms of hypogonadism in patients with MAIS.