Women with
polycystic ovary syndrome (PCOS) are characterized by defects in
insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis. We administered the
insulin-sensitizing agent
troglitazone to 13 obese women with PCOS and
impaired glucose tolerance to determine whether attenuation of
hyperinsulinemia ameliorates these defects. All subjects had
oligomenorrhea,
hirsutism, polycystic ovaries, and hyperandrogenemia. Before and
after treatment with
troglitazone (400 mg daily for 12 weeks), all had 1) a
GnRH agonist (
leuprolide) test, 2) a 75-g oral
glucose tolerance test, 3) a frequently sampled iv
glucose tolerance test to determine the
insulin sensitivity index and the acute
insulin response to
glucose, 4) an oscillatory
glucose infusion to assess the ability of the beta-cell to entrain to
glucose as quantitated by the normalized spectral power for the insulin secretion rate, and 5) measures of fibrinolytic capacity [
plasminogen activator inhibitor type 1 (PAI-1) and
tissue plasminogen activator]. There was no change in body mass index (39.9 +/- 1.4 vs. 40.2 +/- 1.4 kg/m2) or body fat distribution
after treatment. Both the fasting (91 +/- 3 vs. 103 +/- 3 mg/dL; P < 0.001) and 2 h (146 +/- 8 vs. 171 +/- 6 mg/dL; P < 0.02) plasma
glucose concentrations during the oral
glucose tolerance test declined significantly. There was a concordant reduction in
glycosylated hemoglobin to 5.7 +/- 0.1 from a pretreatment level of 6.1 +/- 0.1% (P < 0.03).
Insulin sensitivity increased from 0.58 +/- 0.14 to 0.95 +/- 0.26 10(-5) min-1/pmol.L (P < 0.01)
after treatment as did the disposition index (745 +/- 135 vs. 381 +/- 96; P < 0.05). The ability of the beta-cell to appropriately detect and respond to an oscillatory
glucose infusion improved significantly after
troglitazone treatment; the normalized spectral power for the insulin secretion rate increased to 5.9 +/- 1.1 from 4.3 +/- 0.8 (P < 0.05). Basal levels of total
testosterone (109.3 +/- 15.2 vs. 79.4 +/- 9.8 ng/dL; P < 0.05) and free
testosterone (33.3 +/- 4.0 vs. 21.2 +/- 2.6 pg/mL; P < 0.01) declined significantly after
troglitazone treatment.
Leuprolide-stimulated levels of
17-hydroxyprogesterone,
androstenedione, and total
testosterone were significantly lower posttreatment compared to pretreatment. The reduction in
androgen levels occurred independently of any changes in
gonadotropin levels. A decreased functional activity of PAI-1 in blood (from 12.7 +/- 2.8 to 6.3 +/- 1.4 AU/mL P < 0.05) was associated with a decreased concentration of PAI-1
protein (from 64.9 +/- 9.1 to 44.8 +/- 6.1 ng/mL; P < 0.05). No change in the functional activity of
tissue plasminogen activator (from 5.3 +/- 0.4 to 5.1 +/- 0.5 IU/mL) was observed despite a decrease in its concentration (from 9.6 +/- 0.9 to 8.2 +/- 0.7 ng/mL; P < 0.05). The marked reduction in PAI-1 could be expected to improve the fibrinolytic response to
thrombosis in these subjects. We conclude that administration of
troglitazone to women with PCOS and
impaired glucose tolerance ameliorates the metabolic and hormonal derangements characteristic of the syndrome.
Troglitazone holds potential as a useful primary or adjunctive treatment for women with PCOS.