Statins in the Treatment of Polycystic Ovary Syndrome

ABSTRACT

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting reproductive-aged women. The hyperandrogenemia associated with the syndrome is a result of excessive growth and steroidogenic activity of theca-interstitial tissues in response to various factors, including elevated gonadotropins, hyperinsulinemia, and oxidative stress. PCOS frequently coexists with other cardiovascular risk factors, such as dyslipidemia and systemic inflammation. Statins inhibit the synthesis of mevalonate, the key precursor to cholesterol biosynthesis, and reduce cardiovascular morbidity and mortality. Blockade of mevalonate production may also lead to decreased maturation of insulin receptors, inhibition of steroidogenesis (e.g., via limiting the amount of substrate: cholesterol), and alteration of signal transduction pathways that mediate cellular proliferation. The latter depend upon posttranslational modification of proteins (prenylation), a process mediated by mevalonate derivatives. Statins also have intrinsic antioxidant properties. Given the pleiotropic actions of statins, they are likely not only to improve the dyslipidemia associated with PCOS but may also exert other beneficial metabolic and endocrine effects.

KEYWORDS

PCOS - statin - oxidative stress - insulin resistance - hyperandrogenemia - dyslipidemia - metabolic syndrome

REFERENCES

• 1 Azziz R, Woods K S, Reyna R, Key T J, Knochenhauer E S, Yildiz B O. The prevalence and features of the polycystic ovary syndrome in an unselected population.  J Clin Endocrinol Metab. 2004;  89 2745-2749
• 2 Azziz R, Carmina E, Dewailly E et al.. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline.  J Clin Endocrinol Metab. 2006;  91 4237-4245
• 3 Ehrmann D A, Barnes R B, Rosenfield R L, Cavaghan M K, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome.  Diabetes Care. 1999;  22 141-146
• 4 Legro R S, Kunselman A R, Dodson W C, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women.  J Clin Endocrinol Metab. 1999;  84 165-169
• 5 Ehrmann D A, Kasza K, Azziz R, Legro R S, Ghazzi M N. Effect of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2005;  90 66-71
• 6 Wild R A, Applebaum-Bowden D, Demers L M et al.. Lipoprotein lipids in women with androgen excess: independent associations with increased insulin and androgens.  Clin Chem. 1990;  36 283-289
• 7 Mahabeer S, Naidoo C, Norman R J, Jialal I, Reddi K, Joubert S M. Metabolic profiles and lipoprotein lipid concentrations in non-obese and obese patients with polycystic ovarian disease.  Horm Metab Res. 1990;  22 537-540
• 8 Dahlgren E, Johansson S, Lindstedt G et al.. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones.  Fertil Steril. 1992;  57 505-513
• 9 Dahlgren E, Janson P O, Johansson S, Lapidus L, Oden A. Polycystic ovary syndrome and risk for myocardial infarction.  Acta Obstet Gynecol Scand. 1992;  71 599-604
• 10 Hughesdon P E. Morphology and morphogenesis of the Stein-Leventhal ovary and of so-called “hyperthecosis”.  Obstet Gynecol Surv. 1982;  37 59-77
• 11 Wickenheisser J K, Quinn P G, Nelson V L, Legro R S, Strauss JFr, McAllister J M. Differential activity of the cytochrome P450 17 alpha hydroxylase and steroidogenic acute regulatory protein gene promoters in normal and polycystic ovary syndrome theca cells.  J Clin Endocrinol Metab. 2000;  85 2304-2311
• 12 Nelson V L, Legro R S, Strauss J F, McAllister J M. Augmented androgen production is a stable steroidogenic phenotype of propageted theca cells from polycystic ovaries.  Mol Endocrinol. 1999;  13 946-957
• 13 Yen S S, Vela P, Rankin J. Inappropriate secretion of follicle-stimulating hormone and luteinizing hormone in polycystic ovarian disease.  J Clin Endocrinol Metab. 1970;  30 435-442
• 14 Barbieri R L, Makris A, Ryan K J. Insulin stimulates androgen accumulation in incubations of human ovarian stroma and theca.  Obstet Gynecol. 1984;  64 735-805
• 15 Barbieri R L, Makris A, Randall R W, Daniels G, Kistner R W, Ryan K J. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism.  J Clin Endocrinol Metab. 1986;  62 904-910
• 16 Iwashita M, Mimuro T, Watanabe M et al.. Plasma levels of insulin-like growth factor-I and its binding protein in polycystic ovary syndrome.  Horm Res. 1990;  33(Suppl 2) 21-26
• 17 Homburg R, Pariente C, Lunenfeld B, Jacobs H S. The role of insulin-like growth factor-I (IGF-I) and IGF binding protein in patients with polycystic ovarian disease.  Hum Reprod. 1992;  7 1379-1383
• 18 Suikkari A M, Ruutiainen K, Erkkola R, Seppala M. Low levels of low molecular weight insulin like growth factor binding protein in patients with polycystic ovarian disease.  Hum Reprod. 1989;  4 136-139
• 19 Thierry van Dessel H J, Lee P D, Faessen G, Fauser B C, Giudice L. Elevated serum levels of free insulin-like growth factor I in polycystic ovary syndrome.  J Clin Endocrinol Metab. 1999;  84 3030-3035
• 20 Duleba A J, Spaczynski R Z, Olive D L, Behrman H R. Effects of insulin and insulin-like growth factors on proliferation of rat ovarian theca-interstitial cells.  Biol Reprod. 1997;  56 891-897
• 21 Duleba A J, Spaczynski R Z, Olive D L. Insulin and insulin-like growth factor I stimulate the proliferation of human ovarian theca-interstitial cells.  Fertil Steril. 1998;  69 335-340
• 22 Duleba A J, Spaczynski R Z, Arici A, Carbone R, Behrman H R. Proliferation and differentiation of rat theca-interstitial cells: comparison of effects induced by platelet-derived growth factor and insulin-like growth factor-I.  Biol Reprod. 1999;  60 546-550
• 23 Duleba A J, Spaczynski R Z, Olive D L, Behrman H R. Divergent mechanism regulate proliferation/survival and steroidogenesis of theca-interstitial cells.  Mol Hum Reprod. 1999;  5 193-198
• 24 Duleba A J, Spaczynski R Z, Tilly J L, Olive D L. Insulin and insulin-like growth factors protect ovarian theca-interstitial cells from apoptosis. Presented at: 45th Annual Meeting of the Society for Gynecologic Investigation 1998 Atlanta, GA;
• 25 Nestler J E, Powers L P, Matt D W et al.. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome.  J Clin Endocrinol Metab. 1991;  72 83-89
• 26 Duleba A J, Foyouzi N, Karaca M, Pehlivan T, Kwintkiewicz J, Behrman H R. Proliferation of ovarian theca-interstitial cells is modulated by antioxidants and oxidative stress.  Hum Reprod. 2004;  19 1519-1524
• 27 Gonzalez F, Thusu K, Abdel-Rahman E, Prabhala A, Tomani M, Dandona P. Elevated serum levels of tumor necrosis factor alpha in normal-weight women with polycystic ovary syndrome.  Metabolism. 1999;  48 437-441
• 28 Sabuncu T, Vural H, Harma M. Oxidative stress in polycystic ovary syndrome and its contribution to the risk of cardiovascular disease.  Clin Biochem. 2001;  34 407-413
• 29 Kelly C C, Lyall H, Petrie J R, Gould G W, Connell J M, Sattar N. Low grade chronic inflammation in women with polycystic ovarian syndrome.  J Clin Endocrinol Metab. 2001;  86 2453-2455
• 30 Anderson R N, Smith B L. Deaths: leading causes for 2002.  Natl Vital Stat Rep. 2005;  53 1-89
• 31 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).  Lancet. 1994;  344 1383-1389
• 32 Goldstein J L, Brown M S. Regulation of the mevalonate pathway.  Nature. 1990;  343 425-430
• 33 Clearfield M. Evolution of cholesterol management therapies exploiting potential for further improvement.  Am J Ther. 2003;  10 275-281
• 34 McFarlane S I, Muniyappa R, Francisco R, Sowers J R. Clinical review 145: pleiotropic effects of statins: lipid reduction and beyond.  J Clin Endocrinol Metab. 2002;  87 1451-1458
• 35 Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F. New insignts into the pharmacodynamic and pharmacokinetic properties of statins.  Pharmacol Ther. 1999;  84 413-428
• 36 Albert M A, Staggers J, Chew P, Ridker P M. The pravastatin inflammation CRP evaluation (PRINCE): rationale and design.  Am Heart J. 2001;  141 893-898
• 37 Trochu J N, Mital S, Zhang X et al.. Preservation of NO production by statins in the treatment of heart failure.  Cardiovasc Res. 2003;  60 250-258
• 38 O'Driscoll G, Green D, Taylor R R. Simvastatin, an HMG coenzyme A reductase inhibitor, improves endothelial function within 1 month.  Circulation. 1997;  95 1126-1131
• 39 Porter K E, Naik J, Turner N A, Dickinson T, Thompson M M, London N J. Simvastatin inhibits human saphenous vein neointima formation via inhibition of smooth muscle cell proliferation and migration.  J Vasc Surg. 2002;  36 150-157
• 40 Pierpoint T, McKeigue P, Isaacs A J, Wild S H, Jacobs H. Mortality of women with polycystic ovary syndrome at long-term follow-up.  J Clin Epidemiol. 1998;  51 581-586
• 41 Wild R A, Painter P C, Coulson P B, Carruth K B, Ranney G B. Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 1985;  61 946-951
• 42 Lakhani K, Seifalian A M, Hardiman P. Impaired carotid viscoelastic properties in women with polycystic ovaries.  Circulation. 2002;  106 81-85
• 43 Paradisi G, Steinberg H O, Hempfling A et al.. Polycystic ovary syndrome is associated with endothelial dysfunction.  Circulation. 2001;  103 1410-1415
• 44 Guzick D S, Talbott E O, Sutton-Tyrrell K, Herzog H C, Kuller L H, Wolfson S KJ. Carotid atherosclerosis in women with polycystic ovary syndrome:initial results from a case-control study.  Am J Obstet Gynecol. 1996;  174 1224-1229
• 45 Talbott E, Guzick D S, Clerici A et al.. Coronary heart disease risk factors in women with polycystic ovary syndrome.  Arterioscler Thromb Vasc Biol. 1995;  15 821-826
• 46 Birdsall M A, Farquhar C M, White H D. Association between polycystic ovaries and extent of coronary artery disease in women having cardiac catheterization.  Ann Intern Med. 1997;  126 32-35
• 47 Schneider J G, Tompkins C, Blumenthal R S, Mora S. The metabolic syndrome in women.  Cardiol Rev. 2006;  14 286-291
• 48 Apridonidze T, Essah P A, Iuorno M J, Nestler J E. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2005;  90 1929-1935
• 49 Reaven G M. Banting lecture 1988. Role of insulin resistance in human disease.  Diabetes. 1988;  37 1597-1607
• 50 Conway G S, Agrawal R, Betteridge D J, Jacobs H S. Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome.  Clin Endocrinol (Oxf). 1992;  37 119-125
• 51 Holte J, Bergh T, Berne C, Lithell H. Serum lipoprotein lipid profile in women with the polycystic ovary syndrome: relation to anthropometric, endocrine, and metabolic variables.  Clin Endocrinol (Oxf). 1994;  41 463-471
• 52 Amowitz L L, Sobel B E. Cardiovascular consequences of polycystic ovary syndrome.  Endocrinol Metab Clin North Am. 1999;  28 439-458
• 53 Gambineri A, Pelusi C, Genghini S et al.. Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome.  Clin Endocrinol (Oxf). 2004;  60 241-249
• 54 Diamanti-Kandarakis E, Mitrakou A, Raptis S, Tolis G, Duleba A J. The effect of a pure anti-androgen receptor blocker flutamide on the lipid profile in the polycystic ovary syndrome.  J Clin Endocrinol Metab. 1998;  83 2699-2705
• 55 Loverro G, Lorusso F, Mei L, Depalo R, Cormio G, Selvaggi L. The plasma homocysteine levels are increased in polycystic ovary syndrome.  Gynecol Obstet Invest. 2002;  53 157-162
• 56 Randeva H S, Lewandowski K C, Drzewoski J et al.. Exercise decreases plasma total homocysteine in overweight young women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2002;  87 4496-4501
• 57 Vrbikova J, Bicikova M, Tallova J, Hill M, Starka L. Homocysteine and steroid levels in metformin-treated women with polycystic ovary syndrome.  Exp Clin Endocrinol Diabetes. 2002;  110 74-77
• 58 Yilmaz M, Bukan N, Ayvaz G et al.. The effects of rosiglitazone and metformin on oxidative stress and homocysteine levels in lean patients iwth polycytic ovary syndrome.  Hum Reprod. 2005;  20 3333-3340
• 59 Clark R, Daly L, Robinson K et al.. Hyperhomocysteinemia: an independent risk factor for vascular disease.  N Engl J Med. 1991;  324 1149-1155
• 60 Kanani P, Sinkey C, Browning R, Allaman M, Knapp H, Haynes W. Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocysteinemia in humans.  Circulation. 1999;  100 1161-1168
• 61 Eberhardt R T, Forgione M A, Cap A et al.. Endothelial dysfunction in a murine model of mild hyperhomocysteinemia.  J Clin Invest. 2000;  106 483-491
• 62 Loscalzo J. Oxidant stress: a key determinant of atherothrombosis.  Biochem Soc Trans. 2003;  31 1059-1061
• 63 Ungvari Z, Csiszar A, Edwards J G et al.. Increased superoxide production in coronary arteries in hyperhomocysteinemia: role of TNF-a, NADPH oxidase, and iNOS.  Arterioscler Thromb Vasc Biol. 2003;  23 418-424
• 64 Halliwell B, Gutteridge J M. Free Radicals in Biology and Medicine. Oxford, UK; Clarendon Press 1999
• 65 Paolisso G, Esposito R, D'Alessio M A, Barbieri M. Primary and secondary prevention of atherosclerosis: is there a role for antioxidants?.  Diabetes Metab. 1999;  25 298-306
• 66 Rosen P, Nawroth P P, King G, Moller W, Tritschler H J, Packer L. The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association, and the German Diabetes Society.  Diabetes Metab Res Rev. 2001;  17 189-212
• 67 Orio Jr F, Palomba S, Cascela T et al.. The increase of leukocytes as a new putative marker of low-grade chronic inflammation and early cardiovascular risk in polycystic ovary syndrome.  J Clin Endocrinol Metab. 2005;  90 2-5
• 68 Clement M V, Pervaiz S. Reactive oxygen intermediates regulate cellular response to apoptotic stimuli: a hypothesis.  Free Radic Res. 1999;  30 247-252
• 69 Kamata H, Hirata H. Redox regulation of cellular signalling.  Cell Signal. 1999;  11 1-14
• 70 Kunsch C, Medford R M. Oxidative stress as a regulator of gene expression in the vasculature.  Circ Res. 1999;  85 753-766
• 71 Burdon R H, Alliangana D, Gill V. Hydrogen peroxide and the proliferation of BHK-2 cells.  Free Radic Res. 1995;  23 471-486
• 72 Burdon R H, Gill V, Alliangana D. Hydrogen peroxide in relation to proliferation and apoptosis in BHK-21 hamster fibroblasts.  Free Radic Res. 1996;  24 81-93
• 73 del Bello B, Paolicchi A, Comporti M, Pompella A, Maellaro E. Hydrogen peroxide produced during gamma-glutamyl transpeptidase activity is involved in prevention of apoptosis and maintainance of proliferation in U937 cells.  FASEB J. 1999;  13 69-79
• 74 Spaczynski R Z, Arici A, Duleba A J. Tumor necrosis factor-alpha stimulates proliferation of rat ovarian theca-interstitial cells.  Biol Reprod. 1999;  61 993-998
• 75 Naz R K, Thurston D, Santoro N. Circulating tumor necrosis factor (TNF)-alpha in normally cycling women and patients with premature ovarian failure and polycystic ovaries.  Am J Reprod Immunol. 1995;  34 170-175
• 76 Ruiz-Gines J A, Lopez-Ongil S, Gonzalez-Rubio M, Gonzalez -S L, Rodriguez-Puyol M, Rodriguez-Puyol D. Reactive oxygen species induce proliferation of bovine aortic endothelial cells.  J Cardiovasc Pharmacol. 2000;  35 109-113
• 77 Ivanov V O, Ivanova S V, Niedzwiecki A. Ascorbate affects proliferation of guinea pig vascular smooth muscle cells by direct and extracellular matrix-mediated effects.  J Mol Cell Cardiol. 1997;  29 3293-3303
• 78 Azzi A, Aratri E, Boscoboinik D et al.. Molecular basis of alpha-tocopherol control of smooth muscle cell proliferation.  Biofactors. 1998;  7 3-14
• 79 Nesaretnam K, Stephen R, Dils R, Darbre P. Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status.  Lipids. 1998;  33 461-469
• 80 Onat D, Boscoboinik D, Azzi A, Basaga H. Effects of alpha-tocopherol and silibin dihemisuccinate on the proliferation of human skin fibroblasts.  Biotechnol Appl Biochem. 1999;  29 213-215
• 81 Piotrowski P, Rzepczynska I, Kwintkiewicz J, Duleba A J. Oxidative stress induces expression of CYP11A, CYP17, StAR and 3βHSD in rat theca-interstitial cells. Presented at: 52nd Annual Meeting of the Society for Gynecologic Investigation March 23-26, 2005 Los Angeles, CA;
• 82 Paz K, Voliovitch H, Hadari Y R, Roberts C T, LeRoith D, Zick Y. Interaction between the insulin receptor and its downstream effectors- use of individually expressed receptor domains for structure function analysis.  J Biol Chem. 1996;  271 6998-7003
• 83 Paz K, Hemi R, LeRoith D et al.. A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin- induced tyrosine phosphoryalation.  J Biol Chem. 1997;  272 29911-29918
• 84 Potashnik R, Bloch-Damti A, Bashan N, Rudich A. IRS-1 degradation and increased serine phosphorylation cannot predict the degree of metabolic insulin resistance induced by oxidative stress.  Diabetologia. 2003;  46 639-648
• 85 Evans J L, Maddux B A, Goldfine I D. The molecular basis for oxidative stress-induced insulin resistance.  Antioxid Redox Signal. 2005;  7 1040-1052
• 86 Book C B, Dunaif A. Selective insulin resistance in the polycystic ovary syndrome.  J Clin Endocrinol Metab. 1999;  84 3110-3116
• 87 Corbould A, Zhao H, Mirzoeva S, Aird F, Dunaif A. Enhanced mitogenic signaling in skeletal muscle of women with polycystic ovary syndrome.  Diabetes. 2006;  55 751-759
• 88 Turunen M, Olsson J, Dallner G. Metabolism and function of coenzyme Q.  Biochim Biophys Acta. 2004;  1660 171-199
• 89 Carlberg M, Dricu A, Blegen H et al.. Mevalonic acid is limiting for N-linked glycosylation and translocation of the insulin-like growth factor-I receptor to the cell surface. Evidence for a new link between 3-hydroxy-3-methylglutaryl coenzyme A reductase and cell growth.  J Biol Chem. 1996;  271 17453-17462
• 90 Zhang F L, Casey P J. Protein prenylation: molecular mechanism and functional consequences.  Annu Rev Biochem. 1996;  65 241-269
• 91 Lawlor M A, Alessi D R. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses?.  J Cell Sci. 2001;  114 2903-2910
• 92 Yang C M, Lin M I, Hsieh H L, Sun C C, May Y H, Hsiao L D. Bradykinin-induced p42/p44 MAPK phosphorylation and cell proliferation via Src, EGF receptors, and PI3-K/Akt in vascular smooth muscle cells.  J Cell Physiol. 2005;  203 538-546
• 93 Conejo R, Lorenzo M. Insulin signaling leading to proliferation, survival, and membrane ruffling in C2C12 myoblasts.  J Cell Physiol. 2001;  187 96-108
• 94 Kurihara S, Hakuno F, Takahashi S. Insulin-like growth factor-I-dependent signal transduction pathways leading to the induction of cell growth and differentiation of human neuroblastoma cell line SH-SY5Y: the roles of MAP kinase pathway and PI 3-kinase pathway.  Endocr J. 2000;  47 739-751
• 95 Goalstone M L, Leitner J W, Wall K et al.. Effect of insulin on farnesyltransferase. Specificity of insulin action and potentiation of nuclear effects of insulin-like growth factor-1, epidermal growth factor, and platelet-derived growth factor.  J Biol Chem. 1998;  273 23892-23896
• 96 Goalstone M L, Draznin B. Effect of insulin on farnesyltransferase activity in 3T3-L1 adipocytes.  J Biol Chem. 1996;  271 27585-27589
• 97 Goalstone M L, Leitner J W, Golovchenko I et al.. Insulin promotes phosphorylation and activation of geranylgeranyltransferase II. Studies with geranylgeraylation of rab-3 and rab-4.  J Biol Chem. 1999;  274 2880-2884
• 98 Barbieri R L, Makris A, Ryan K J. Effects of insulin on steroidogenesis in cultured porcine ovarian theca.  Fertil Steril. 1983;  40 237-241
• 99 McCarty M F. Insulin's stimulation of endothelial superoxide generation may reflect up-regulation of isoprenyl transferase activity that promotes rac translocation.  Med Hypotheses. 2002;  58 472-475
• 100 Draznin B, Miles P, Kruszynska Y et al.. Effects of insulin on prenylation as a mechanism of potentially detrimental influence of hyperinsulinemia.  Endocrinology. 2000;  141 1310-1316
• 101 Goalstone M L, Draznin B. What does insulin do to Ras?.  Cell Signal. 1998;  10 297-301
• 102 Solomon C S, Leitner J W, Goalstone M L. Dominant negative alpha-subunit of farnesyl- and geranylgeranyl-transferase I inhibits insulin-induced differentiation of 3T3-L1 pre-adipocytes.  Int J Obes Relat Metab Disord. 2003;  27 40-47h
• 103 Lee W C, Choi C H, Cha S H, Oh H L, Kim Y K. Role of ERK in hydrogen peroxide-induced cell death of human glioma cells.  Neurochem Res. 2005;  30 263-270
• 104 Wassmann S, Laufs U, Muller K et al.. Cellular antioxidant effects of atorvastatin in vitro and in vivo.  Arterioscler Thromb Vasc Biol. 2002;  22 300-305
• 105 Gregg D, Rauscher F M, Goldschmidt-Clermont P J. Rac regulates cardiovascular superoxide through diverse molecular interactions: more than a binary GTP switch.  Am J Physiol Cell Physiol. 2003;  285 C723-C734
• 106 Wu C H, Chen Y F, Wang J Y et al.. Mutant K-ras oncogene regulates steroidogenesis of normal human adrenocortical cells by the RAF-MEK-MAPK pathway.  Br J Cancer. 2002;  87 1000-1005
• 107 Wu C H, Lee S C, Chiu H H et al.. Morphologic change and elevation of cortisol secretion in cultured human normal adrenocortical cells caused by mutant p21K-ras protein.  DNA Cell Biol. 2002;  21 21-29
• 108 Izquierdo D, Foyouzi N, Kwintkiewicz J, Duleba A J. Mevastatin inhibits ovarian theca-interstitial cell proliferation and steroidogenesis.  Fertil Steril. 2004;  82 1193-1197
• 109 Kwintkiewicz J, Foyouzi N, Piotrowski P, Rzepczynska I, Duleba A J. Mevastatin inhibits proliferation of rat ovarian theca-interstitial cells by blocking the mitogen activated protein kinase pathway.  Fertil Steril. 2006;  86 1053-1058
• 110 Axel D I, Riessen R, Runge H, Viebahn R, Karsch K R. Effects of cerivastatin on human arterial smooth muscle cell proliferation and migration in transfilter cocultures.  J Cardiovasc Pharmacol. 2000;  35 619-629
• 111 Buemi M, Allegra A, Senatore M et al.. Pro-apoptotic effect of fluvastatin on human smooth muscle cells.  Eur J Pharmacol. 1999;  370 201-203
• 112 El-Ani D, Zimlichman R. Simvastatin induces apoptosis of cultured rat cardiomyocytes.  J Basic Clin Physiol Pharmacol. 2001;  12 325-338
• 113 Danesh F R, Sadeghi M M, Amro N et al.. 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/p21 signaling pathway: implications for diabetic nephropathy.  Proc Natl Acad Sci U S A. 2002;  99 8301-8305
• 114 Wu C H, Lee S C, Chiu H H et al.. Morphologic change and elevation of cortisol secretion in cultured human normal adrenocortical cells caused by mutant p21K-ras protein.  DNA Cell Biol. 2002;  21 21-29
• 115 Dobs A S, Schrott H, Davidson M H et al.. Effects of high-dose simvastatin on adrenal and gonadal steroidogenesis in men with hypercholesterolemia.  Metabolism. 2000;  49 1234-1238
• 116 Rzepczynska I, Piotrowski P, Kwintkiewicz J, Duleba A J. Effect of mevastatin on expression of CYP17, 3bHSD, CYP11A and StAR in rat theca-interstitial cells. Presented at: 52nd Annual Meeting of the Society for Gynecologic Investigation March 23-26, 2005 Los Angeles, CA;
• 117 Piotrowski P, Kwintkiewicz J, Rzepczynska I, Duleba A J. Simvastatin and mevastatin inhibit expression of NADPH oxidase subunits: p22phox and p47phox in rat theca-interstitial cells. Presented at: 52nd Annual Meeting of the Society for Gynecologic Investigation March 23-26, 2005 Los Angeles, CA;
• 118 Hernandez R, Teruel T, Lorenzo M. Akt mediates insulin induction of glucose uptake and up-regulation of GLUT4 gene expression in brown adipocytes.  FEBS Lett. 2001;  494 225-231
• 119 Welsh G I, Hers I, Berwick D C et al.. Role of protein kinase B in insulin-regulated glucose uptake.  Biochem Soc Trans. 2005;  33 346-349
• 120 Duleba A J, Banaszweska B, Spaczynski R Z, Pawelczyk L. Simvastatin improves biochemical parameters of polycystic ovary syndrome: results of a prospective randomized trial.  Fertil Steril. 2006;  85 996-1001
• 121 Banaszewska B, Pawelczyk L, Spaczynski R Z, Dziura J, Duleba A J. Effects of simvastatin and oral contraceptive agent on polycystic ovary syndrome: prospective randomized cross-over trial.  J Clin Endocrinol Metab.. 2006;  92 456-461