SAT-291 Gonadotropin Releasing Hormone Agonist Therapy Improves Hyperandrogenism in an Adolescent with Type A Insulin Resistance Syndrome

Abstract

Background: Type A insulin resistance (IR) is a form of severe IR due to heterozygous mutations in the insulin receptor gene. It presents with acanthosis nigricans, IR, and hyperandrogenism in the absence of obesity or lipodystrophy. Treatment aims to decrease androgens and improve insulin sensitivity. We describe the first adolescent patient with Type A IR having successful resolution of clinical and biochemical hyperandrogenism during GnRH agonist treatment. Clinical Case: An adolescent female was referred for secondary amenorrhea and hirsutism. She had a normal BMI and prominent hirsutism. Laboratories revealed LH 11.6 mIU/mL, FSH 4.2 mIU/mL, elevated total and free testosterone 96 and 2.21 ng/dL, respectively, normal glucose and HbA1c (5.6 %). She was diagnosed with PCOS and referred for OGTT as per standard care in our PCOS program. Fasting glucose was 80 mg/dL with fasting insulin level of 63.1 mIU/mL. The 2-hour glucose was 199 mg/dL with insulin level of 1480 uIU/mL. Pelvic ultrasound showed enlarged ovaries. Due to hyperandrogenism with severe IR, dysglycemia, and normal lipids, Type A IR was entertained. Genetic testing revealed a heterozygous mutation in the insulin receptor gene for a missense variant pointing towards the diagnosis of Type A IR.The patient had been prescribed treatment with metformin and spironolactone although her adherence to taking her medications was sporadic. She was then trialed on an oral contraceptive which led to monthly menstrual cycles. However, her total and free testosterone levels remained elevated at 139 and 3.06 ng/dL respectively. Her hirsutism had not improved which led to prominent depression. Twelve months from her initial presentation, the decision was made to try treatment with leuprolide and she subsequently began 11.25 mg/month intramuscular injections. She continued metformin as well. One month after her first leuprolide injection, follow-up labs showed normalization of total and free testosterone levels, 7.1 and 0.16 ng/dL respectively, and decreased LH of 0.3 mIU/mL. Hirsutism was markedly improved. Five months into leuprolide therapy, repeat OGTT still showed impaired glucose tolerance and severe IR (0-minute glucose of 91 mg/dL, insulin of 90.9 uIU/mL; 2-hour glucose of 181 mg/dL, insulin of 1038 uIU/mL) along with increased HbA1c (6.4%). Conclusion: We describe an adolescent patient with Type A IR who experienced resolution of hyperandrogenism during GnRH agonist treatment. The bidirectional relationship between insulin and hyperandrogenism including insulin having LH-independent effects on steroidogenesis has been debated. Given our patient’s reduction in testosterone and hirsutism despite persistent hyperinsulinism, this case challenges the idea that insulin increases steroidogenesis independently of gonadotropins. GnRH agonist therapy should be considered to improve hyperandrogenism in severe cases of IR.