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Direct Thiazolidinedione Action in the Human Ovary: Insulin-Independent and Insulin-Sensitizing Effects on Steroidogenesis and Insulin-Like Growth Factor Binding Protein-1 Production

Division of Endocrinology, Departments of Medicine (D.S.-Y., M.P., J.S., D.A., P.P., L.P.) and Obstetrics and Gynecology (A.P., K.H., P.C.), Beth Israel Medical Center and Albert Einstein College of Medicine, New York, New York 10003; and Institute of Biology and Immunology of Reproduction (D.A.), Bulgarian Academy of Sciences, Sofia, Bulgaria, 1113

Address all correspondence and requests for reprints to: Leonid Poretsky, M.D., or Donna Seto-Young, Ph.D., Division of Endocrinology, Beth Israel Medical Center, 317 East 17th Street, Fierman Hall, Seventh Floor, New York, New York 10003. E-mail: lporetsk{at}bethisraelny.org or dyoung{at}chpnet.org.

Context and Objective: Hyperinsulinemia contributes to the pathogenesis of ovarian dysfunction in insulin-resistant states, including polycystic ovary syndrome (PCOS). Peroxisome proliferator activated receptor- (PPAR-) agonists [thiazolidinediones (TZDs)] ameliorate hyperandrogenism in polycystic ovary syndrome presumably because they reduce systemic hyperinsulinemia. Direct effects of TZDs in the ovary, however, cannot be excluded. We explored direct effects of TZDs in cultured human ovarian cells.

Methods: Human ovarian cells, obtained from oophorectomy specimens, were cultured in the presence or absence of rosiglitazone or pioglitazone, insulin, and gonadotropins. Steroid hormone and IGF-binding protein-1 (IGFBP-1) concentrations were measured in conditioned tissue culture medium.

Results: Rosiglitazone or pioglitazone stimulated progesterone production up to 156% (P < 0.001) and 131% (P < 0.001) of baseline, respectively. Pioglitazone but not rosiglitazone, inhibited baseline and FSH-stimulated estradiol production by 20% (P < 0.001) and 50% (P < 0.001), respectively. Both rosiglitazone and pioglitazone abolished insulin-dependent stimulation of estradiol production in the presence of FSH. Rosiglitazone and pioglitazone inhibited testosterone production by 10% (P < 0.012) and 15% (P < 0.023), respectively, and abolished insulin-induced stimulation of testosterone production. In the absence of insulin, pioglitazone or rosiglitazone stimulated IGFBP-1 production up to 160% (P < 0.001) and 125% (P < 0.036) of baseline, respectively. Pioglitazone and rosiglitazone enhanced insulin-induced inhibition of IGFBP-1 production by 13% and 20%, respectively (P < 0.001).

Conclusions: PPAR- agonists directly stimulate progesterone and IGFBP-1 production, inhibit estradiol and testosterone production, abolish insulin-induced stimulation of testosterone production and insulin-dependent stimulation of estradiol production in the presence of FSH, and enhance insulin-induced inhibition of IGFBP-1 production in human ovarian cells. PPAR- represents a novel system of ovarian regulation.

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