Metabolic and other effects of pioglitazone as an add-on therapy to metformin in the treatment of polycystic ovary syndrome (PCOS)

Hormones

Volumn 12, Issue 3, 2013, Pages 363-378

  Valsamakis, Georgios ^a,b   Lois, Kostas ^a   Kumar, Sudhesh ^a   Mastorakos, George ^b  

^a UNIVERSITY HOSPITALS COVENTRY AND WARWICKSHIRE NHS TRUST   (United Kingdom)

^b UNIVERSITY OF ATHENS   (Greece)

Author keywords

Metabolic; Metformin; PCOS; Pioglitazone; Reproductive

Indexed keywords

CYPROTERONE ACETATE PLUS ETHINYLESTRADIOL; FLUTAMIDE; METFORMIN; PIOGLITAZONE; PLACEBO; ROSIGLITAZONE;

ABDOMINAL CRAMP; ADD ON THERAPY; ATHEROSCLEROSIS; COMBINATION CHEMOTHERAPY; DIARRHEA; DISEASE ASSOCIATION; DRUG EFFECT; DRUG EFFICACY; DRUG RESPONSE; DRUG SAFETY; DYSLIPIDEMIA; HEMATOCRIT; HUMAN; HYPERANDROGENISM; HYPOGLYCEMIA; INSULIN RESISTANCE; LIVER TOXICITY; MONOTHERAPY; NAUSEA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OVARY POLYCYSTIC DISEASE; PHARMACEUTICAL CARE; REVIEW; SIDE EFFECT; TREATMENT OUTCOME; WEIGHT GAIN;

DIABETES MELLITUS, TYPE 2; FEMALE; HUMANS; HYPERANDROGENISM; HYPERINSULINISM; INSULIN RESISTANCE; METFORMIN; POLYCYSTIC OVARY SYNDROME; THIAZOLIDINEDIONES;

EID: 84885209519     PISSN: 11093099     EISSN: None     Source Type: Journal    
DOI: 10.1007/bf03401302     Document Type: Review

References (122)

1. Diamanti-Kandarakis E, Kouli CR, Bergiele AT, et al, 1999 A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 84: 4006-4011.
2. Azziz R, Carmina E, Dewailly D, et al, 2009 The androgen excess and pcos society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 91: 456-488.
3. Elting MW, Korsen TJ, Bezemer PD, Schoemaker J, 2001 Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population. Hum Reprod 16: 556-560.
4. Legro RS, Kunselman AR, Dodson WC, Dunaif A, 1999 Prevalence and predictors of risk for type 2 diabetes and impaired glucose tolerance in polycystic ovary syndrome: A prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 84: 165-169.
5. Talbott EO, Zborowski JV, Rager JR, et al, 2004 Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome. J Clin Endocrinol Metab 89: 5454-5461.
6. Christakou CD, Diamanti-Kandarakis E, 2008 Role of androgen excess on metabolic aberrations and cardiovascular risk in women with polycystic ovary syndrome. Womens Health (Lond Engl) 4: 583-594.
7. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004 Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81: 19-25.
8. Azziz R, Carmina E, Dewailly D, et al, 2006 Positions statement criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an androgen excess society guideline. J Clin Endocrinol Metab 91: 4237-4245.
9. Dunaif A, Segal KR, Shelley DR, et al, 1992 Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 41:1257-1266.
10. Taylor SI, Cama A, Accili D, et al, 1992 Mutations in the insulin receptor gene. Endocr Rev 13: 566-595.
11. Dunaif A, 1992 Insulin resistance and ovarian hyperandrogenism. The Endocrinologist 2: 248-260.
12. Willis D, Mason H, Gilling-Smith C, et al, 1996 Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J Clin Endocrinol Metab 81: 302-309.
13. Diamanti-Kandarakis E, Dunaif A, 2012 Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 33: 981-1030.
14. Tosi F, Negri C, Perrone F, et al, 2012 Hyperinsulinemia amplifies GnRH agonist stimulated ovarian steroid secretion in women with polycystic ovary syndrome. J Clin Endocrinol Metab 97: 1712-1719.
15. Blank SK, McCartney CR, Chhabra S, et al, 2009 Modulation of gonadotrophin releasing hormone pulse generator sensitivity to progesterone inhibition in hyperandrogenic adolescent girls-implications for regulation of pubertal maturation. J Clin Endocrinol Metab 94: 2630-2636.
16. Burt Solorzano CM, Beller JP, Abshire MY, et al, 2012 Neuroendocrine dysfunction in polycystic ovary syndrome. Steroids 77: 332-337.
17. Dewailly D, Pigny P, Soudan B, et al, 2010 Reconciling the definitions of polycystic ovary syndrome: the ovarian follicle number and serum anti-Mullerian hormone concentrations aggregate with the markers of hyperandrogenism. J Clin Endocrinol Metab 95: 4399-4405.
18. Desforges-Bullet V, Gallo C, Lefebre C, et al, 2010 Increased anti-Mullerian hormone and decreased FSH levels in follicular fluid obtained in women with polycystic ovaries at the time of follicle puncture for in vitro fertilization. Fertil Steril 94: 198-204.
19. Homburg R, Ray A, Bhide P, et al, 2013 The relationship of serum anti-Mullerian hormone with polycystic ovarian morphology and polycystic ovary syndrome: a prospective cohort study. Hum Reprod 28: 1077-1083.
20. Pierre A, Peigne M, Grynberg M, 2013 Loss of LH induced down regulation of anti-Mullerian hormone receptor expression may contribute to anovulation in women with polycystic ovary syndrome. Hum Reprod 28: 762-769.
21. El-Roeiy A, Chen X, Roberts VJ, 1993 Expression of insulin-like growth factor-I (IGF-I) and IGF-II and the IGF-I, IGF-II, and insulin receptor genes and localization of the gene products in the human ovary. J Clin Endocrinol Metab 77: 1411-1418.
22. Kelly CJ, Stenton SR, Lashen H, 2011 Insulin-like growth factor binding protein-1 in PCOS: a systematic review and meta-analysis. Hum Reprod Update 17: 4-16.
23. Bailey CJ, Turner RC, 1996 Metformin. N Engl J Med 334: 574.
24. Dresner A, Laurent D, Marcucci M, et al, 1999 Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 103: 253-259.
25. Matthaei S, Hamann A, Klein HH, et al, 1992 Evidence that metformin increases insulin-stimulated glucose transport by potentiating insulin-induced translocation of glucose transporters from an intracellular pool to the cell surface in rat adipocytes. Horm Metab Res Suppl 26: 34-41.
26. Musi N, Hirshman MF, Nygren J, et al, 2002 Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51: 2074-2081.
27. Goldstein BJ, 1999 Current views on the mechanism of action of thiazolidinedione insulin sensitizers. Diabetes Technol Ther 1: 267-275.
28. de Souza CJ, Eckhardt M, Gagen K, et al, 2001 Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance. Diabetes 50: 1863-1871.
29. Arner P, 2003 The adipocytes in insulin resistance: key molecules and the impact of the thiazolidinediones. Trends Endocrinol Metab 14: 137-145.
30. Yamauchi T, Kamon J, Waki H, et al, 2001 The mechanism by which both heterozygous peroxisome proliferator-activated receptor gamma (ppargamma) deficiency and ppargamma agonist improve insulin resistance. J Biol Chem 276: 41245-41254.
31. Hirose H, Kawai T, Yamamoto Y, et al, 2002 Effects of pioglitazone on metabolic parameters, body fat distribution, and serum adiponectin levels in Japanese male patients with type 2 diabetes. Metabolism 51: 314-317.
32. Minako I, Kensuke E, Ken-ichi H, et al, 2002 Antiinflammatory and Antiarteriosclerotic Effects of Pioglitazone. Hypertension 40: 687-693.
33. DeFronzo AR, Banerji M, Bray GA, et al, 2009 Actos Now for the prevention of diabetes (ACT NOW) study. BMC Endocr Disord 9: 17.
34. Steven E, Nissen MD, Kathy Wolski MPH, 2007 Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med 356: 2457-2471.
35. Home P, Pocock S, Beck-Nielsen H, Curtis P, Gomis R, Hanefeld M, (RECORD Study Team), 2009 Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373: 2125-2135.
36. Riche D, Valderrama R, Henyan N, 2007 Thiazolidinediones and Risk of Repeat Target Vessel Revascularization Following Percutaneous Coronary Intervention. A meta-analysis. Diabetes Care 30: 384-388.
37. Nathan DM, Buse JB, Davidson MB, et al, 2009 Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diab Care 32: 193-203.
38. Nissen SE, Nicholls SJ, Wolski K, et al, 2008 Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 299: 1561-1573.
39. Dormandy JA, Charbonnel B, Eckland DJ, et al, 2005 Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in macroVascular Events): a randomised controlled trial. Lancet 366: 1279-1289.
40. Goldberg RB, Kendall DM, Deeg MA, et al, 2005 A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 28: 1547-1554.
41. Lago RM, Singh PP, Nesto RW, 2007 Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 370: 1129-1136.
42. Ferrara A, Lewis JD, Quesenberry CP Jr, et al, 2011 Cohort Study of Pioglitazone and Cancer Incidence in Patients With Diabetes. Diabetes Care 34: 923-929.
43. Marks D, 2013 Drug utilization, safety and clinical use of Actos and Avandia. Int J Risk Saf Med 25: 39-51.
44. Beck GR Jr, Khazai NB, Bouloux GF, et al, 2013 The effects of thiazolidinediones on human bone marrow stromal cell differentiation in vitro and in thiazolidinedione-treated patients with type 2 diabetes. Transl Res 161: 145-155.
45. Aubert RE, Herrera V, Chen W, et al, 2010 Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes. Diabetes Obes Metab 12: 716-722.
46. Berria R, Glass L, Mahankali A, et al, 2007 A Reduction in hematocrit and hemoglobin following pioglitazone treatment is not hemodilutional in Type II diabetes mellitus. Clin Pharmacol Ther 82: 275-281.
47. Expert Panel on, Detection, Evaluation, and Treatment of High Blood Cholesterol in, Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel II) 2001 JAMA 285: 2486.
48. Grundy SM, Hansen B, Smith SC Jr, et al, 2004 American Heart Association; National Heart, Lung, and Blood Institute; American Diabetes Association, Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management. Circulation 109: 551-556.
49. Rosenzweig JL, Ferrannini E, Grundy SM, et al, 2008 Primary prevention of cardiovascular disease and type 2 diabetes in patients at metabolic risk: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93: 3671-3689.
50. Velazquez EM, Mendoza S, Hamer T, et al, 1994 Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 43: 647-654.
51. Dunaif A, Scott D, Finegood D, et al, 1996 The insulin sensitizing agent troglitazone: a novel therapy for the polycystic ovary syndrome. J Clin Endocrinol Metab 81: 3299-3306.
52. Ehrmann DA, Schneider DJ, Sobel BE, et al, 1997 Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 82: 2108-2116.
53. Romualdi D, Guido M, Ciampelli M, et al, 2003 Selective effects of pioglitazone on insulin and androgen abnormalities in normo-and hyperinsulinaemic obese patients with polycystic ovary syndrome. Hum Reprod 18: 1210-1218.
54. Nestler JE, 2008 Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med 358: 47-54.
55. Nestler JE, Jakubowicz DJ, 1996 Decreases in ovarian cytochrome p450c17 activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 335: 617-623.
56. Moghetti P, Castello R, Negri C, et al, 2000 Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 85: 139-146.
57. Fleming R, Hopkinson ZE, Wallace AM, et al, 2002 Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab 87: 569-574.
58. Pasquali R, Gambineri A, Biscotti D, et al, 2000 Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab 85: 2767-2774.
59. Lord JM, Flight IH, Norman RJ, 2003 Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 327: 951-953.
60. Lord J, Thomas R, Fox B, et al, 2006 The effect of metformin on fat distribution and the metabolic syndrome in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. BJOG 113: 817-824.
61. Banaszewska B, Duleba AJ, Spaczynski RZ, et al, 2006 Lipids in polycystic ovary syndrome: role of hyperinsulinemia and effects of metformin. Am J Obstet Gynecol 194: 1266-1272.
62. Palomba S, Falbo A, Russo T, et al, 2007 Insulin sensitivity after metformin suspension in normal-weight women with polycystic ovary syndrome. J Clin Endocrinol Metab 92: 3128-3135.
63. Ziaee A, Oveisi S, Abedini A, et al, 2012 Effect of metformin and pioglitazone treatment on cardiovascular risk profile in polycystic ovary syndrome. Acta Med Indones 44: 16-22.
64. Agarwal N, Rice SP, Bolusani H, et al, 2010 Metformin reduces arterial stiffness and improves endothelial function in young women with polycystic ovary syndrome: a randomized, placebo-controlled, crossover trial. J Clin Endocrinol Metab 95: 722-730.
65. Heutling D, Schulz H, Nickel I, et al, 2008 Asymmetrical dimethylarginine, inflammatory and metabolic parameters in women with polycystic ovary syndrome before and after metformin treatment. J Clin Endocrinol Metab 93: 82-90.
66. Aubuchon M, Lieman H, Stein D, et al, 2009 Metformin does not improve the reproductive or metabolic profile in women with polycystic ovary syndrome (PCOS). Reprod Sci 16: 938-946.
67. Luque-Ramirez M, Mendieta-Azcona C, Alvarez-Blasco F, Escobar-Morreale HF, 2009 Effects of metformin versus ethinyl-estradiol plus cyproterone acetate on ambulatory blood pressure monitoring and carotid intima media thickness in women with the polycystic ovary syndrome. Fertil Steril 91: 2527-2536.
68. Palomba S, Falbo A, Zullo F, Orio F Jr, 2009 Evidencebased and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr Rev 30: 1-50.
69. Katsiki N, Georgiadou E, Hatzitolios A, 2009 The role of insulin-sensitizing agents in the treatment of polycystic ovary syndrome. Drugs 69: 1417-1431.
70. Diamanti-Kandarakis E, Spina G, Kouli C, Migdalis I, 2001 Increase in endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin treatment. J Clin Endocrinol Metab 86: 4666-4673.
71. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J, 1999 Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 22: 141-146.
72. Glueck CJ, Wang P, Kobayashi S, Phillips H, Sieve-Smith L, 2002 Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril 77: 520-525.
73. Gilbert C, Valois M, Koren G, 2006 Pregnancy outcome after first-trimester exposure to metformin: a metaanalysis. Fertil Steril 86: 658-663.
74. International Diabetes Federation Clinical Guidelines Task Force, 2009 Global guideline on pregnancy and diabetes. brussels, belgium: international diabetes federation. Available at: http://www.idf.org/global-guidelinepregnancy-and-diabetes. Accessed April 1, 2010
75. Glintborg D, Højlund K, Andersen NR, Hansen BF, Beck-Nielsen H, Wojtaszewski JF, 2008 Impaired insulin activation and dephosphorylation of glycogen synthase in skeletal muscle of women with polycystic ovary syndrome is reversed by pioglitazone treatment. J Clin Endocrinol Metab 93: 3618-3626.
76. Aroda RV, Ciaraldi TP, Burke P, et al, 2008 Metabolic and hormonal changes induced by pioglitazone in polycystic ovary syndrome: a randomized, placebo-controlled clinical trial. J Clin Endocrinol Metab 94: 469-476.
77. Mather KJ, Funahashi T, Matsuzawa Y, et al, 2008 Diabetes prevention program adiponectin, change in adiponectin, and progression to diabetes in the diabetes prevention program. Diabetes 57: 980-986.
78. Laughlin GA, Barrett-Connor E, May S, Langenberg C, 2007 Association of adiponectin with coronary heart disease and mortality: the Rancho Bernardo study. Am J Epidemiol 165: 164-174.
79. Glintborg D, Højlund K, Andersen M, Henriksen JE, Beck-Nielsen H, Handberg A, 2008 Soluble CD36 and risk markers of insulin resistance and atherosclerosis are elevated in polycystic ovary syndrome and significantly reduced during pioglitazone treatment. Diabetes Care 31: 328-334.
80. Brettenthaler N, De Geyter C, Huber PR, Keller U, 2004 Effect of the insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome. J Clin Endocrinol Metab 89: 3835-3840.
81. Aigner E, Bachofner N, Klein K, 2009 Retinol-Binding Protein 4 in polycystic ovary syndrome-association with steroid hormones and response to pioglitazone treatment. The J Clin Endocrinol Metab 94: 1229-1235.
82. Asadipooya K, Kalantar-Hormozi M, Nabipour I, 2012 Pioglitazone reduces central obesity in polycystic ovary syndrome women. Gynecol Endocrinol 28: 16-19.
83. Rao LN, Jacob JJ, Paul TV, Rajarathinam S, Thomas N, SeShadri MS, 2008 Effects of pioglitazone on menstrual frequency, hyperandrogenism and insulin resistance in adolescents and young adults with polycystic ovary syndrome. J Pediatr Adolesc Gynecol 22: 91-95.
84. Romualdi D, Giuliani M, Cristello F, et al, 2010 Metformin effects on ovarian ultrasound appearance and steroidogenic function in normal-weight normoinsulinemic women with polycystic ovary syndrome: a randomized double-blind placebo controlled trial. Fertil Steril 93: 2303-2310.
85. Genazzani AD, Battaglia C, Malavasi B, Strucchi C, Tortolani F, Gamba O, 2004 Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome. Fertil Steril 81: 114-119.
86. Kazerooni T, Ghaffarpasand F, Kazerooni Y, Kazerooni M, Setoodeh S, 2009 Short-term metformin treatment for clomiphene citrate-resistant women with polycystic ovary syndrome. Int J Gynaecol Obstet 107: 50-53.
87. Palomba S, Falbo A, Orio F Jr, et al, 2005 A randomized controlled trial evaluating metformin pre-treatment and co-administration in non-obese insulin-resistant women with polycystic ovary syndrome treated with controlled ovarian stimulation plus timed intercourse or intrauterine insemination. Hum Reprod 20: 2879-2886.
88. Stadtmauer LA, Toma SK, Riehl RM, Talbert LM, 2001 Metformin treatment of patients with polycystic ovary syndrome undergoing in vitro fertilization improves outcomes and is associated with modulation of the insulin-like growth factors. Fertil Steril 75: 505-509.
89. Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P, 2001 Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril 75: 46-52.
90. Thatcher SS, Jackson EM, 2006 Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin. Fertil Steril 85: 1002-1009.
91. Ehrmann DA, Cavaghan MK, Imperial J, et al, 1997 Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 82: 524-530.
92. Nestler JE, Jakubowicz DJ, Reamer P, Gunn RD, Allan G, 1999 Ovulatory and metabolic effects of D-chiroinositol in the polycystic ovary syndrome. N Engl J Med 340: 1314-1320.
93. Oppelt PG, Mueller A, Jentsch K, et al, 2009 The effect of metformin treatment for 2 years without caloric restriction on endocrine and metabolic parameters in women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 118: 633-637.
94. Kelly CJ, Gordon D, 2002 The effect of metformin on hirsutism in polycystic ovary syndrome. Eur J Endocrinol 147: 217-221.
95. Cosma M, Swiglo BA, Flynn DN, Kurtz DM, Labella ML, Mullan RJ, 2008 Clinical review: Insulin sensitizers for the treatment of hirsutism: a systematic review and metaanalyses of randomized controlled trials. J Clin Endocrinol Metab 93: 1135-1142.
96. Martin KA, Chang RJ, Ehrmann DA, et al, 2008 Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93: 1105-1120.
97. Glintborg D, Hermann AP, Andersen M, et al, 2006 Effect of pioglitazone on glucose metabolism and luteinizing hormone secretion in women with polycystic ovary syndrome. Fertil Steril 86: 385-397.
98. Coffler MS, Patel K, Dahan MH, Yoo RY, Malcom PJ, Chang RJ, 2003 Enhanced granulosa cell responsiveness to follicle-stimulating hormone during insulin infusion in women with polycystic ovary syndrome treated with pioglitazone. J Clin Endocrinol Metab 88: 5624-5631.
99. Arlt W, Auchus RJ, Miller WL, 2001 Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes p450c17 and 3b-hydroxysteroid dehydrogenase. J Biol Chem 276: 16767-16771.
100. Stout DL, Fugate SE, 2005 Thiazolidinediones for treatment of polycystic ovary syndrome. Pharmacotherapy 25: 244-252.
101. Glintborg D, Hermann AP, Hagen C, et al, 2009 A randomized placebo-controlled study on the effects of pioglitazone on cortisol metabolism in polycystic ovary syndrome. Fertil Steril 91: 842-850.
102. Seto-Young D, Paliou M, Schlosser J, et al, 2005 Direct thiazolidinedione action in the human ovary: insulin-independent and insulin-sensitizing effects on steroidogenesis and insulin-like growth factor binding protein-1 production. J Clin Endocrinol Metab 90: 6099-6105.
103. Glintborg D, Støving RK, Hagen C, et al, 2005 Pioglitazone treatment increases spontaneous growth hormone (GH) secretion and stimulated GH levels in polycystic ovary syndrome. J Clin Endocrinol Metab 90: 5605-5612.
104. Kim CH, Jeon GH, Kim SR, Kim SH, Chae HD, Kang BM, 2010 Effects of pioglitazone on ovarian stromal blood flow, ovarian stimulation, and in vitro fertilization outcome in patients with polycystic ovary syndrome. Fertil Steril 94: 236-241.
105. Glintborg D, Hermann AP, Brusgaard K, Hangaard J, Hagen C, Andersen M 2005 Significantly Higher Adrenocorticotropin-Stimulated Cortisol and 17-Hydroxyprogesterone Levels in 337 Consecutive, Premenopausal, Caucasian, Hirsute Patients Compared with Healthy Controls. J Clin Endocrinol Metab 90: 1347-1353.
106. Zhang LH, Rodriguez H, Ohno S, Miller WL, 1995 Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Nat Acad Sci USA 92: 10619-10623.
107. Fassnacht M, Schlenz N, Schneider SB, Wudy SA, Allolio B, Arlt W, 2003 Beyond adrenal and ovarian androgen generation: Increased peripheral 5 alphareductase activity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 88: 2760-2766.
108. Walker BR, Aggarwal I, Stewart PM, Padfield PL, Edwards CR, 1995 Endogenous inhibitors of 11 betahydroxysteroid dehydrogenase in hypertension. J Clin Endocrinol Metab 80: 529-533.
109. Romualdi D, Giuliani M, Draisci G, et al, 2007 Pioglitazone reduces the adrenal androgen response to corticotropin-releasing factor without changes in ACTH release in hyperinsulinemic women with polycystic ovary syndrome. Fertil Steril 88: 131-138.
110. Tsilchorozidou T, Honour JW, Conway GS, 2003 Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates. J Clin Endocrinol Metab 88: 5907-5913.
111. Li XJ, Yu YX, Liu CQ, et al, 2011 Metformin vs thiazolidinediones for treatment of clinical, hormonal and metabolic characteristics of polycystic ovarysyndrome: a meta-analysis. Clin Endocrinol (Oxf) 74: 332-339.
112. Einhorn D, Rendell M, Rosenzweig J, Egan JW, Mathisen AL, Schneider RL. 2000 Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. The Pioglitazone 027 Study Group. Clin Ther 22: 1395-1409.
113. Ortega-Gonzalez C, Luna S, Hernandez L, et al, 2005 Responses of serum androgen and insulin resistance to metformin and pioglitazone in obese, insulin-resistant women with polycystic ovary syndrome. J Clin Endocrinol Metab 90: 1360-1365.
114. Naka KK, Kalantaridou SN, Kravariti M, Bechlioulis A, Kazakos N, Calis KA, 2011 Effect of the insulin sensitizers metformin and pioglitazone on endothelial function in young women with polycystic ovary syndrome: a prospective randomized study. Fertil Steril 95: 203-209.
115. Ibáñez L, López-Bermejo A, Díaz M, Enríquez G, del Río L, de Zegher F, 2009 Low-dose pioglitazone and low-dose flutamide added to metformin and oestro-progestagens for hyperinsulinaemic women with androgen excess: add-on benefits disclosed by a randomized double-placebo study over 24 months. Clin Endocrinol (Oxf) 71: 351-357.
116. Ibáñez L, López-Bermejo A, del Rio L, Enríquez G, Valls C, de Zegher F, 2007 Combined low-dose pioglitazone, flutamide, and metformin for women with androgen excess. J Clin Endocrinol Metab 92: 1710-1714.
117. Talbot JA, Bicknell EJ, Rajkhowa M, Krook A, O'Rahilly S, Clayton RN, 1996 Molecular scanning of the insulin receptor gene in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 81: 1979-1983.
118. Gupta AK, Bray GA, Greenway FL, Martin CK, Johnson WD, Smith SR, 2010 Pioglitazone, but not Metformin reduces liver fat in Type-2 diabetes mellitus independent of weight changes. J Diabetes Complications 24: 289-296.
119. Glueck CJ, Moreira A, Goldenberg N, Sieve L, Wang P, 2003b Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin. Hum Reprod 18: 1618-1625.
120. Ota H, Goto T, Yoshioka T, Ohyama N, 2008 Successful pregnancies treated with pioglitazone in infertile patients with polycystic ovary syndrome. Fertil Steril 90:709-13
121. Ibáñez L, Díaz M, Sebastiani G, Marcos MV, López-Bermejo A, de Zegher F, 2013 Oral contraception vs insulin sensitization for 18 months in non-obese adolescents with androgen excess: posttreatment differences in c-reactive protein, intima-media thickness, visceral adiposity, insulin sensitivity, and menstrual regularity. J Clin Endocrinol Metab 98: E902-907.
122. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2008 Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril 89: 505-522.