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

Discussion

We describe a case of an adolescent girl with type A IR whose severe hirsutism and biochemical hyperandrogenism were successfully managed on GnRH agonist therapy, despite extreme hyperinsulinemia. Our patient's dysglycemia and extreme hyperinsulinemia led to genetic testing, which revealed a mutation in the insulin receptor gene [c.3095G>A(pGly1032Asp)]. Although the direct causality cannot be proven, we suspect the mutation is pathogenic because it fits the patient's clinical picture of type A IR and was not present in the asymptomatic mother's genetic testing (asymptomatic father not available for testing). The amino acid residue pGly1032 is highly conserved during evolution, and no missense variants at this codon have previously been reported. Yet other heterozygous missense variants in this domain have been reported pathogenic in severe IR.[6]

This case allowed us to examine the frequently debated bidirectional relationship between insulin and hyperandrogenism, often deemed independent of gonadotropin activity. Insulin can act directly on theca cells to drive testosterone production.[3] Even in patients with insulin receptor defects, ovarian sensitivity to insulin remains conserved. It is postulated that excess insulin activates the similarly structured IGF-1 receptors, leading to ovarian hyperandrogenism.[7] Therefore, in the case of severe IR syndromes, we may expect hyperandrogenism to persist even after the gonadotropin stimulus is suppressed. However, our case showed clinical and biochemical hyperandrogenism that responded dramatically to leuprolide despite persistent hyperinsulinism. Our case suggests that LH is necessary to facilitate insulin's action on steroidogenesis even in severe IR due to a defective insulin receptor. A similar conclusion was drawn in the aforementioned case by Brown et al.,[4] which demonstrated the permissive effect of LH in a patient with autoimmune type B IR. Hyperandrogenemia itself can lead to IR, but data are inconsistent on the impact of decreasing androgens in improving insulin sensitivity.[3] Some patients with PCOS and mild IR have shown modest improvements in insulin sensitivity during androgen suppression with GnRH agonists.[8] In our case, prominent IR persisted after marked testosterone suppression.

Of note, our patient's diagnosis of severe IR would have been missed if OGTT had not been performed. OGTT is not routinely performed in the setting of normal HbA1c, fasting glycemia, and BMI. Supported by previous findings of abnormal glucose tolerance in nonobese adolescents with hyperandrogenism,[9] we argue OGTT should be considered in all patients with hyperandrogenism.

The utility of transabdominal ultrasound for the evaluation of adolescent reproductive health is controversial.[5] There has been some support for use of ovarian size measurement (reviewed in[10]]). However, the relevance of follicle counts has remained questionable because of a lack of normative data during adolescence as gathered via modern ultrasound technology. We observed an increase in ovarian volume meeting the adult definition of PCOM in association with persistent hyperandrogenism. Normalization of ovarian volume occurred with resolution of hyperandrogenism. This observation is consistent with ovarian size reflecting hyperandrogenism in adolescents.[10] Transabdominal ultrasound may be helpful in monitoring progression or resolution of hyperandrogenism, particularly in cases where access to reliable biochemical assays is limited.

In conclusion, we present a case of an adolescent with a mutation in the insulin receptor gene whose hyperandrogenism responded to GnRH agonist therapy. Her persistent, severe IR brings into question the mechanism of insulin causing hyperandrogenism independently of LH. GnRH agonist therapy may be helpful in cases of severe IR syndromes with distressing hirsutism when other modalities are unsuccessful.

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