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Submitted on March 3, 2005
Accepted on August 23, 2005
Division of Endocrinology, Department of Medicine, and Department of Obstetrics and Gynecology, Beth Israel Medical Center and Albert Einstein College of Medicine, New York, NY 10003; Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Sofia, Bulgaria
* To whom correspondence should be addressed. E-mail: dyoung{at}chpnet.org or lporetsk{at}bethisraelny.org.
Context and objective. Hyperinsulinemia contributes to the pathogenesis of ovarian dysfunction in insulin resistant states, including polycystic ovary syndrome (PCOS). PPAR-
agonists (thiazolidinediones, TZDs) ameliorate hyperandrogenism in PCOS 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 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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thiazolidinediones •
ovary
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