Functional adrenal
hyperandrogenism occurs in women with
polycystic ovary syndrome (PCOS).
Insulin, similar to its ovarian effect, may impact the regulation of adrenal steroidogenesis by modulating the activity of P450c17alpha, the rate-limiting
enzyme in
androgen biosynthesis. We previously demonstrated that obese adolescents with PCOS are severely
insulin resistant and are at heightened risk for
impaired glucose tolerance 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. Fifteen 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/m(2).min)-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 tolerance. 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 increased (21.5 +/- 2.2 vs. 25.0 +/- 2.2 micromol/kg.min; P = 0.041). Fasting
insulin and oral
glucose tolerance test
insulin and
glucose area under the curve decreased significantly.
ACTH-stimulated 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 lowering 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, placebo-controlled studies will determine whether
insulin-sensitizing
therapy corrects not only ovarian
hyperandrogenism but also functional adrenal
hyperandrogenism in adolescents with PCOS.