Rosiglitazone and Pioglitazone Inhibit Estrogen Synthesis in Human Granulosa Cells by Interfering with Androgen Binding to Aromatase

Abstract

The effects of rosiglitazone or pioglitazone (thiazolidinediones, TZDs) on estrogen production and aromatase activity in human ovarian cells were examined. Human granulosa cells were incubated in the tissue culture medium supplemented with androstenedione or testosterone, with or without insulin, TZDs, or type 1 17β-hydroxysteroid-dehydrogenase (17β-HSD) inhibitor. Estrogen concentrations in the conditioned medium, aromatase mRNA and protein expression in the cells and androgen substrate binding to aromatase were measured. With androstenedione as substrate, rosiglitazone or pioglitazone inhibited estrone production by up to 22% (p<0.012) while type 1 17β-HSD inhibitor enhanced this effect of rosiglitazone or pioglitazone by 37% (p<0.001) and by 67% (p<0.001), respectively. With testosterone as substrate, rosiglitazone or pioglitazone inhibited estradiol production by 32% (p<0.001). With ³H-testosterone as substrate, rosiglitazone or pioglitazone inhibited the ³H-tritiated water release by the cultured cells by 45% and 35%, respectively, thus directly demonstrating inhibition of aromatase. Rosiglitazone or pioglitazone, however, had no significant effect on aromatase mRNA or protein expression. Rosiglitazone or pioglitazone inhibited ¹²⁵I-androstenedione and ¹²⁵I-testosterone binding to aromatase by 38% (p<0.001). It was concluded that rosiglitazone or pioglitazone inhibit estrogen synthesis in human granulosa cells by interfering with androgen binding to aromatase.

thiazolidinediones - estrogens - aromatase - insulin sensitivity - PPAR-γ - polycystic ovary syndrome

References

• 1 Dronavalli S, Ehrmann DA. Pharmacologic therapy of polycystic ovary syndrome.  Clin Obstetr Gynecol. 2007;  50 244-254
• 2 Brettenthaler N, DeGeyter C, Huber PR, Keller U. Effect of the insulin sensitizer pioglitazone treatment on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2004;  89 3835-3840
• 3 Sepilian V, Nagamani M. Effects of rosiglitazone in obese women with polycystic ovary syndrome and severe insulin resistance.  J Clin Endocrinol Metab. 2005;  90 60-65
• 4 Legro RS, Zaino RJ, Demers LM, Kunselman AR, Gnatuk CL, Williams NI, Dodson WC. The effects of metformin and rosiglitazone, alone and in combination, on the ovary and endometrium in polycystic ovary syndrome.  Am J Obstet Gynecol. 2007;  196: 402 e1-e10
• 5 Seto-Young D, Paliou M, Schlosser J, Avtanski D, Park A, Patel P, Holcomb K, Chang P, Poretsky L. Direct thiazolidinedione action in the human ovary: insulin-independent and insulin-sensitizing effects in steroidogenesis and insulin-like growth factor binding protein-1 production.  J Clin Endocrinol Metab. 2005;  90 6099-6105
• 6 Gasic S, Bodenburg Y, Nagamani M, Green A, Urban RJ. Troglitazone inhibits progesterone production in porcine granulosa cells.  Endocrinology. 1998;  139 4962-4966
• 7 Fan WQ, Yanase T, Morinaga H, Mu YM, Nomura M, Okabe T, Goto K, Harada N, Nawata H. Activation of peroxisome proliferator-activated receptor-γ and retinoid X receptor inhibits aromatase transcription via nuclear factor-κB.  Endocrinology. 2005;  146 85-92
• 8 Mu YM, Yanase T, Nishi Y, Waseda N, Oda T, Tanaka A, Takayanagi R, Nawata H. Insulin sensitizer, troglitazone, directly inhibits aromatase activity in human ovarian granulosa cells.  Boichem Biophys Res Commun. 2000;  271 710-713
• 9 Seto-Young D, Zajac J, Liu H-C, Rosenwaks Z, Poretsky L. The role of mitogen activated protein kinase (MAPK) in insulin and IGF-I signaling cascades for progesterone and IGFBP-1 production in human granulosa cells.  J Clin Endocrinol Metab. 2003;  88 3385-3391
• 10 Baltlhazart J, Baillien M, Ball GF. Interactions between kinase and phosphatases in the rapid control of brain aromatase.  J Neuroendocrinol. 2005;  17 553-559
• 11 Seto-Young D, Avtanski D, Strizhevsky M, Parikh G, Patel P, Kaplun J, Holcomb K, Rosenwaks Z, Poretsky L. Interactions among peroxisome proliferator activated receptor-γ: Insulin signaling pathways, and steroidogenic acute regulatory protein in human ovarian cells.  J Clin Endocrinol Metab. 2007;  92 2232-2239
• 12 Bloomgarden ZT, Futterweit W, Poretsky L. Use of insulin-sensitizing agents in patients with polycystic ovary syndrome.  Endocrine Practice. 2001;  7 279-286
• 13 Schwartz AV, Sellermeyer DE, Vittinghoff E, Palermo L, Lecka-Czernik B, Feingold KR, Strotmeyer ES, Resnick HE, Carbone L, Beamer BA, Park SW, Lane NE, Harris TB, Cummings SR. Thiazolidinedione use and bone loss in older diabetic adults.  J Clin Endocrinol Metab. 2006;  91 3349-3354
• 14 Grey A, Bolland M, Gamble G, Wattie D, Horne A, Davidson J, Reid IR. The peroxisome proliferator activated receptor-γ agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial.  J Clin Endocrinol Metab. 2007;  92 1305-1310
• 15 Habbi ZA, Havstad SL, Wells K, Divine G, Pladevall M, Williams LK. Thiazolidinedione use and the longitudinal risk of fractures in patients with type 2 Diabetes Mellitus.  J Clin Endocrinol Metab. 2010;  95 592-600
• 16 Davies GF, McFie PJ, Khandelwal RL, Roesler WJ. Unique ability of troglitazone to up-regulate peroxisome proliferator-activated receptor-γ expression in hepatocytes.  J Pharmacol Exp Therapeu. 2002;  300 72-77
• 17 Prueksaritanont T, Vega JM, Zhao J, Gagliano K, Kuznetsova O, Musser B, Amin RD, Liu L, Roadcap BA, Dilzer KC, Lasseter S, Rogers JD. Interaction between simvastain and troglitazone or pioglitazone in healthy subjects.  J Clin Pharmacol. 2001;  41 573-581
• 18 Messinis IE. Ovulation induction.  Hum Reprod. 2005;  20 2688-2697
• 19 Rubin GL, Zhao Y, Kalus AM, Simpson ER. Peroxisome proliferator activated receptor-γ ligands inhibit estrogen biosynthesis in human breast adipose tissue: Possible implication for breast cancer therapy.  Cancer Res. 2000;  60 1604-1608
• 20 De Dios ST, Bruemmer D, Dilley RJ, Ivey EM, Jennings GLR, Law RE, Little PJ. Inhibitory activity of clinical thiazolidinedione peroxisome proliferator activating receptor-γ ligands toward internal mammary artery, radial artery, and saphenous vein smooth muscle cell proliferation.  Circulation. 2003;  107 2548-2550
• 21 Karaer Ö, Oruç S, Koyuncu FM. Aromatase inhibitors: possible future applications.  Acta Obstet Gynecol Scand. 2004;  83 699-706

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