Metformin Therapy in Obese Adolescents with Polycystic Ovary Syndrome and Impaired Glucose Tolerance: Amelioration of Exaggerated Adrenal Response to Adrenocorticotropin with Reduction of Insulinemia/Insulin Resistance

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Abstract
Functional adrenal hyperandrogenism occurs in women with polycystic ovary syndrome (PCOS). Insulin, similar to its ovar- ian effect, may impact the regulation of adrenal steroidogen- esis by modulating the activity of P450c17, the rate-limiting enzyme in androgen biosynthesis. We previously demon- strated that obese adolescents with PCOS are severely insulin resistant and are at heightened risk for impaired glucose tol- erance and type 2 diabetes. In the present study we tested the hypothesis that metformin therapy in obese adolescents with PCOS will attenuate the adrenal steroidogenic response to ACTH, with reduction of insulin resistance/insulinemia. Fif- teen adolescents with PCOS and impaired glucose tolerance received 3 months of metformin (850 mg, twice daily) therapy. Pre- and posttherapy they had oral glucose tolerance testing, ACTH stimulation test, a 3-h hyperinsulinemic (80 mU/ m2min)-euglycemic clamp to assess insulin sensitivity and a hyperglycemic clamp to assess insulin secretion. After 3 months of metformin treatment, glucose intolerance improved, with eight subjects having normal glucose toler- ance. Total and free T decreased (1.5 0.2 vs. 1.0 0.1 nmol/ liter (P 0.022) and 41.3 8.3 vs. 22.2 2.1 pmol/liter (P 0.028), respectively). Insulin-stimulated glucose disposal in- creased (21.5 2.2 vs. 25.0 2.2 mol/kgmin; P 0.041). Fast- ing insulin and oral glucose tolerance test insulin and glucose area under the curve decreased significantly. ACTH-stimu- lated increases in androstenedione, 17-hydroxyprogesterone, and 17-hydroxypregnenelone were lower after metformin treatment (2.8 0.4 vs. 1.7 0.3 nmol/liter (P 0.014), 7.0 0.6 vs. 5.3 0.5 nmol/liter (P 0.011), and 30.4 3.7 vs. 25.7 4.2 nmol/liter (P 0.054)). Fasting insulin correlated with the 17-hydroxypregnenelone response to ACTH stimulation (r 0.52; P 0.008). In summary, metformin treatment of obese adolescents with PCOS and impaired glucose tolerance is beneficial in improving glucose tolerance and insulin sensitivity, in low- ering insulinemia, and in reducing elevated androgen levels. Moreover, metformin therapy is associated with attenuation of the adrenal steroidogenic response to ACTH. Metformin therapy was well tolerated. In conclusion, double blind, pla- cebo-controlled studies will determine whether insulin- sensitizing therapy corrects not only ovarian hyperandro- genism but also functional adrenal hyperandrogenism in adolescents with PCOS. (J Clin Endocrinol Metab 87: 1555-1559, 2002)

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