GnRH Agonist Improves Hyperandrogenism in an Adolescent Girl With an Insulin Receptor Gene Mutation

Emily Paprocki; Romina L. Barral; Heidi Vanden Brink; Marla Lujan; Tania S. Burgert

Disclosures

J Endo Soc. 2019;3(6):1196-1200. 

In This Article

Abstract and Introduction

Abstract

Type A insulin resistance (IR) is caused by heterozygous mutations in the insulin receptor gene. It presents with mild acanthosis nigricans, severe IR, and hyperandrogenism in the absence of obesity or lipodystrophy. Treatment aims to improve insulin sensitivity and decrease androgens. An adolescent girl was evaluated for secondary amenorrhea and prominent hirsutism. She had a normal body mass index, and laboratory testing revealed an elevated LH to FSH ratio (LH 11.6 mIU/mL, FSH 4.2 mIU/mL), testosterone 96 ng/dL (reference range <50 ng/dL), free testosterone 2.21 ng/dL (reference range <1.09 ng/dL), normal glucose, and HbA1c of 5.6%. She received a diagnosis of polycystic ovary syndrome (PCOS) and was referred to our Multi-Specialty Adolescent PCOS Program. There, oral glucose tolerance test showed fasting glucose and insulin of 80 mg/dL and 63.1 mIU/mL, respectively. The 2-hour glucose and insulin were 199 mg/dL and 1480 μIU/mL, respectively. Because of hyperandrogenism with severe IR, dysglycemia, and normal lipids, type A IR was considered. Genetic testing revealed a heterozygous mutation in the insulin receptor gene [c.3095G>A(pGly1032Asp)]. After standard treatment of hirsutism and hyperinsulinism failed, a trial of GnRH agonist therapy improved hyperandrogenism and reduced ovarian size while severe IR persisted. We describe an adolescent with type A IR who experienced resolution of clinical and biochemical hyperandrogenism during GnRH agonist treatment. Given the patient's marked reduction in testosterone and hirsutism despite persistent hyperinsulinism, this case challenges the idea that insulin increases steroidogenesis independently of gonadotropin effect. GnRH agonist therapy should be considered in the treatment of hyperandrogenism in severe cases of IR.

Introduction

Type A insulin resistance (IR) is severe IR caused by heterozygous mutations in the insulin receptor gene. It presents after puberty with acanthosis nigricans, IR, and hyperandrogenism.[1] Hyperandrogenism in type A IR may result from insulin acting as a cogonadotropin directly increasing androgen synthesis in theca cells via ovarian insulin receptor signaling[2] or indirectly by increasing GnRH-mediated LH release from the pituitary.[3] Clinical hyperandrogenism is a concern for patients, yet there are limited data on treatment options in severe IR syndromes. In a recently published case of type B insulin resistance masquerading as ovarian hyperthecosis, GnRH agonist treatment curtailed hyperandrogenism without ameliorating diabetes.[4] Similarly, we describe an adolescent patient with type A IR who demonstrated resolution of hyperandrogenism during GnRH agonist treatment while severe IR persisted. This case challenges the notion that insulin increases steroidogenesis independently of gonadotropins.

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