Lack of Hirsutism in an XX Woman With History of Hyperandrogenism and Oligomenorrhea: Two Coexisting Disorders or Novel Syndrome of Androgen Insensitivity?

Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in women, and its etiologies have not been clearly elucidated. Non-classical congenital adrenal hyperplasia (NC-CAH) with mild to moderate enzyme deficiency of 21-hydroxylase due to bi-allelic mutations in its gene (CYP21A2) is a cause of secondary PCOS that should always be considered. Common clinical features of NC-CAH include menstrual irregularities, hirsutism, acne, advanced bone age with accelerated linear growth, and short stature, associated with hyperandrogenism. Androgen insensitivity syndrome (AIS) is another cause of hyperandrogenism due to lack of response to androgen typically in genetic male (XY) presenting with female physical characteristics, most commonly due to a mutation in the androgen receptor (AR) gene on the X chromosome. Here, we present a 61 years old woman, with a diagnosis of PCOS based on oligomenorrhea and high testosterone ~90 pg/mL at age 18, meeting both NIH and Rotterdam PCOS diagnostic criteria. She took oral contraceptive pills only for one year, despite continued menstrual irregularities. After age 42, her menstrual cycles became and remained regular without further intervention until menopause at age 51, while her testosterone levels fluctuated between 80 and 250 pg/mL. After menopause, her testosterone levels drastically increased to >350 pg/mL. The patient has been recommended, but reluctant to undergo oophorectomy for enlarged non-cystic ovaries. Other potentially related clinical features include the presence of a pituitary adenoma, and a thyroid nodule. She has no notable adrenal mass or myelolipoma. Patient is lean and well-fit, at 5’11” and 151 lb. The most puzzling feature has been a lack of virilization and hirsutism. During laboratory evaluation, high 17-hydroxyprogesterone was identified, and NC-CAH became a potential etiology of PCOS, but this did not explain the lack of apparent virilization. The finding of unimpressive levels of DHEA implied that this pathway probably was unlikely the major cause of high testosterone. Investigation for hyperandrogenism focusing on AIS revealed normal female karyotype XX, and no identifiable mutations or abnormal copy number in AR. The findings thus far have provided no unifying diagnosis for her clinical features, especially for androgen insensitivity, and additional studies are being performed. Assessment of other genes recently reported to be associated with AIS is being performed as well as genetic confirmation of NC-CAH by analyzing CYP21A2. Steroid 5-alpha reductase 2 (SRD5A2), whose mutations and polymorphism interestingly are associated with AIS and PCOS, respectively, and nuclear receptor subfamily 5, group A, member 1 (NR5A1) is another gene associated with AIS. It remains to be determined whether she has AIS as a coexisting disorder with NC-CAH or a novel syndrome with a feature of androgen insensitivity.