Long-Term Follow Up and Treatment of a Female with Complete Estrogen Insensitivity.

CONTEXT: We previously reported the first female with a causative ESR1 gene mutation, who exhibited absent puberty, high estrogens, and multicystic ovaries. At age 15 years, she presented with lower abdominal pain, absent breast development, primary amenorrhea, and multicystic ovaries. The natural history of complete estrogen insensitivity (CEI) in women is unknown. OBJECTIVE: The purpose of this report is to present the neuroendocrine phenotype of CEI, identify potential ligands, and determine the effect of targeted treatment. DESIGN: We have characterized gonadotropin pulsatility and followed her endocrine profile and bone density over eight years. Seventy-five different compounds were tested for transactivation of the mutant receptor. A personalized medicine approach was tailored to our patient. SETTING: Academic medical center. PATIENT OR OTHER PARTICIPANTS: 24-year-old, adopted white female with CEI. INTERVENTION(: s): The patient was treated with Diethylstilbestrol (DES) for ~2.5 years. MAIN OUTCOME MEASURE(S): Induction of secondary sexual characteristics. RESULTS: Luteinizing hormone (LH) pulse studies demonstrated normal pulsatile LH secretion, elevated mean LH and mildly elevated mean follicle stimulating hormone (FSH) in the presence of markedly increased estrogens. DES transactivated the mutant ESR1 in vitro. However, DES treatment did not induce secondary sexual characteristics in our patient. CONCLUSIONS: Treatment with DES was not successful in our patient. She remains hypoestrogenic despite the presence of ovarian cysts with a hypoestrogenic vaginal smear, absent breast development, and low bone mineral mass. Findings suggest additional receptor mechanistic actions are required to elicit clinical hormone responses.