Metabolic and hormonal changes induced by pioglitazone in polycystic ovary syndrome: a randomized, placebo-controlled clinical trial

Abstract

Context: Polycystic ovary syndrome (PCOS) is characterized by insulin resistance, compensatory hyperinsulinemia, increased prevalence of impaired glucose tolerance, and increased ovarian androgen biosynthesis.

Objective: The aim of the study was to evaluate effects of pioglitazone on whole body insulin action and ovarian androgen biosynthesis in PCOS.

Design: We performed a randomized placebo-controlled trial.

Setting: The study was conducted at the Special Diagnostic and Treatment Unit of the Veterans Affairs Medical Center, San Diego, and the University of California, San Diego, General Clinical Research Center.

Patients or other participants: A total of 23 subjects with PCOS were evaluated at baseline and end of treatment. Six age- and body mass index-matched women without PCOS were normal controls for baseline evaluation.

Intervention: Subjects with PCOS were randomized to oral placebo or pioglitazone 45 mg daily for 6 months.

Main outcome measure(s): The primary outcome measures were whole body insulin action as measured by hyperinsulinemic euglycemic clamp and ovarian androgen biosynthesis as measured by leuprolide-stimulated production of 17-hydroxyprogesterone (17-OHP).

Results: Compared with placebo, pioglitazone treatment significantly improved multiple measures of insulin action, including glucose disposal rate (P < 0.01), 2-h glucose during 75-g oral glucose tolerance test (P < 0.01), area under the curve glucose during oral glucose tolerance test (P < 0.01), serum adiponectin (P < 0.01), and fasting hyperinsulinemia (P < 0.01). Compared to placebo, pioglitazone treatment reduced the increment of leuprolide-stimulated 17-OHP (P < 0.02). Improvements in glucose disposal rate correlated with reductions in 17-OHP stimulation (P < 0.02).

Conclusions: Compared to placebo, pioglitazone treatment in PCOS was associated with improvements in insulin action and glucose homeostasis and ameliorated the hyperandrogenic ovarian response.

Figure 1

Glucose tolerance curves after 75-g oral glucose challenge in subjects with PCOS before and after 6 months of placebo (n = 10) (A) and subjects with PCOS before and after 6 months of pioglitazone 45 mg/d (n = 13) (B). To convert glucose to SI units, multiply by the conversion factor 0.05551. Data are depicted as mean ± sem. *, P < 0.05.

Figure 2

Change in insulin sensitivity with pioglitazone treatment. A, Change in GDR during hyperinsulinemic euglycemic clamp after 6 months of treatment with placebo or pioglitazone. B, Change in circulating serum adiponectin levels before and after 6 months of placebo or pioglitazone (Pio) treatment. Data are depicted as mean ± sem. *, P < 0.05.

Figure 3

A, Correlation between baseline GDR during hyperinsulinemic euglycemic clamp and increment of leuprolide-stimulated 17OH progesterone. B, Correlation of improvement in GDR during hyperinsulinemic euglycemic clamp with attenuation of leuprolide-stimulated 17-OHP responses. C, Change in increment of leuprolide-stimulated 17-OHP with 6 months of treatment with placebo or pioglitazone. D, Correlation of baseline GDR and SHBG. E, Correlation of improvement in GDR with improvement in SHBG. F, Correlation of change in GDR with change in fasting insulin. To convert 17-OHP to SI units, multiply by the conversion factor 3.03. *, P < 0.05.