Der Einsatz oraler Antidiabetika in der Behandlung des Polyzystischen Ovarsyndroms

Zusammenfassung

Das Polyzystische Ovarsyndrom (PCOS) ist die häufigste endokrine Erkrankung der Frau in der reproduktiven Lebensphase. Es ist ein komplexes Krankheitsbild mit metabolischen Störungen und ihren Langzeitfolgen. Als gesundheitliche Spätfolge droht die Entwicklung eines Diabetes mellitus Typ 2, der gemeinsam mit der häufig vorkommenden Adipositas und Dyslipidämie zu einem erhöhten Risiko kardiovaskulärer Erkrankungen führt. Die Insulinresistenz mit konsekutiver Hyperinsulinämie spielt eine Schlüsselrolle in der Pathophysiologie des PCOS.
Vor diesem Hintergrund erscheint eine Behandlung des PCOS durch orale Antidiabetika sinnvoll. Die Mehrzahl der Studien zeigte, dass diese Medikamente zu einer Verbesserung der typischen Symptome wie dem Hyperandrogenismus und der Zyklusunregelmäßigkeiten führten. Die Ovulations- und Schwangerschaftsraten wurden gesteigert. Darüber hinaus konnten kardioprotektive Wirkungen und eine verbesserte Insulinsensitivität, die möglicherweise auch beim PCOS vor der Entwicklung eines Diabetes mellitus Typ 2 schützt, nachgewiesen werden. Die vorliegende Übersicht beleuchtet den Einsatz verschiedener oraler Antidiabetika beim PCOS und ihren Einfluss auf die Fertilität, die drohende Entwicklung eines Diabetes mellitus und das Risiko kardiovaskulärer Erkrankungen.

Abstract

The polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. It is a complex metabolic-endocrine disorder with severe long-term health consequences like type 2 diabetes. The increased risk for cardiovascular diseases in women with PCOS is due to diabetes, adipositas and dyslipidemia. Insulin resistance plays a key role in the pathophysiology of this syndrome.
This makes the use of oral antidiabetic drugs most compelling. The majority of studies have shown a melioration of the typical symptoms like hyperandrogenism and cycle irregularities. Ovulation and pregnancy rates increased. Furthermore these drugs might be cardioprotective by improving insulin sensitivity and reduce the risk for type 2 diabetes. This article reviews the use of different oral antidiabetic drugs in the treatment of PCOS and their influence on fertility, the risk for type 2 diabetes and cardiovascular diseases.

Polyzystische Ovarsyndrom (PCOS) - Hyperinsulinämie - orale Antidiabetika - Diabetes mellitus Typ 2

Polycystic ovary syndrome (PCOS) - hyperinsulinemia - oral antidiabetic drugs - type 2 diabetes

Literatur

• 1 Acbay O, Gundogdu S. Can metformin reduce insulin resistance in polycystic ovary syndrome?.  Fertil Steril. 1996;  65 946-949
• 2 Amowitz L L, Sobel B E. Cardiovascular consequences of polycystic ovary syndrome.  Endocrinol Metab Clin North Am. 1999;  28 439-458
• 3 Azziz R, Ehrmann D A, Legro R S, Whitcomb R W, Hanley R, Fereshetian A G, O'Keefe M, Ghazzi M N. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial.  J Clin Endocrinol Metab. 2001;  86 1626-1632
• 4 Azziz R, Ehrmann D A, Legro R S, Fereshetian A G, O'Keefe M, Ghazzi M N. Troglitazone decreases adrenal androgen levels in women with polycystic ovary syndrome.  Fertil Steril. 2003;  79 932-937
• 5 Bailey C J, Puah J A. Effect of metformin and glucose metabolism in mouse soleus muscle.  Diabet Metab. 1986;  12 212-218
• 6 Bailey C J, Turner R C. Metformin.  N Engl J Med. 1996;  334 574-579
• 7 Barbieri R L, Smith S, Ryan K J. The role of hyperinsulinemia in the pathogenesis of ovarian hyperandrogenism.  Fertil Steril. 1988;  50 197-212
• 8 Barbieri R L. Metformin for the treatment of polycystic ovary syndrome.  Obstet Gynecol. 2003;  1001 785-793
• 9 Bischoff H. The mechanism of alpha-glucosidase inhibition in the managment of diabetes.  Clin Invest Med. 1995;  18 303-311
• 10 Buchanan T A, Xiang A H, Peters R K, Kjos S L, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis H N, Azen S P. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women.  Diabetes. 2002;  51 2796-2803
• 11 Cavaghan M, Ehrmann D, Byrne M, Polonsky K. Treatment with the oral antidiabetic agent troglitazone improves ß-cell responses to glucose in subjects with impaired glucose tolerance.  J Clin Invest. 1997;  100 530-537
• 12 Ciaraldi T P, El Roeiy A, Madar Z, Reichhart D, Olefsky J M, Yen S S. Cellular mechanisms of insulin resistance in polycystic ovarian syndrome.  J Clin Endocrinol Metab. 1992;  75 577-583
• 13 Ciotta L, Calogero A E, Farina M, DeLeo V, La Marca A, Cianci A. Clinical, endocrine and metabolic effects of acarbose, an alpha-glucosidase inhibitor, in PCOS patients with increased insulin response and normal glucose tolerance.  Hum Reprod. 2001;  16 2066-2072
• 14 Coetzee E J, Jackson W P. Oral hypoglycaemics in the first trimester and fetal outcome.  Afr Med J. 1984;  65 635-637
• 15 Conn J J, Jacobs H S, Conway G S. The prevalence of polycystic ovaries in women with type 2 diabetes mellitus.  Clin Endocrinol. 2000;  52 81
• 16 Crave J C, Fimbel S, Lejeune H, Cugnardey N, Dechaud H, Pugeat M. Effects of diet and metformin administration on sex hormone binding globulin, androgens and insulin in hirsute and obese women.  J Clin Endocrinol Metab. 1995;  80 2057-2062
• 17 Dahlgren E, Janson P O, Johansson S, Lapidus L, Oden A. Polycystic ovary syndrome and risk for myocardial infarcation. Evaluated from a risk factor model based on a prospective population study of women.  Acta Obstet Gynecol Scand. 1992;  71 599-604
• 18 Dahlgren E, Janson P O, Johansson S, Lapidus L, Lindstedt G, Tengborn L. Hemostatic and metabolic variables in women with polycystic ovary syndrome.  Fertil Steril. 1994;  61 445-460
• 19 DeLeo V, la Marca A, Ditto A, Morgante G, Cianci A. Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome.  Fertil Steril. 1999;  72 282-285
• 20 Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A. Therapeutic effects of metformin in insulin resistance and hyperandrogenism in polycystic ovary syndrome.  Eur J Endocrinol. 1998;  138 269-274
• 21 Diamanti-Kandarakis E, Spina G, Kouli C, Migdalis I. Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy.  J Clin Endocrinol Metab. 2001;  86 4466-4473
• 22 Dunaif A, Segal K R, Futterweit W, Dobransky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome.  Diabetes. 1989;  38 1165-1174
• 23 Dunaif A, Xia J, Book C B, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome.  Clin Endocrinol. 1995;  20 643-648
• 24 Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin-sensitizing agent troglitazone improves metabol and reproductive abnormalities in the polycystic ovary syndrome.  J Clin Endocrinol Metab. 1996;  81 3299-3306
• 25 Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis.  Endocr Rev. 1997;  18 774-780
• 26 Ehrmann D, Schneider D, Sobel B, Cavaghan M, Imperial J, Rosenfield R, Polonsky K. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidgenesis and fibrinolysis in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 1997;  82 2108-2116
• 27 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
• 28 Ehrmann D A, Cavaghan M K, Imperial J, Sturis J, Rosenfield R L, Polonsky K S. Effects of metformin on insulin secretion, insulin action and ovarian steriodogenesis with polycystic ovary syndrome.  J Clin Endocrinol Metab. 1997;  82 524-530
• 29 Fantus I G, Brosseau R. Mechanism of action of metformin: insulin receptor and postreceptor effects in vitro and in vivo.  J Clin Endocrinol Metab. 1986;  63 898-905
• 30 Fleming R, Hopkinson Z E, Wallace A M, Greer I A, Sattar N. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial.  J Clin Endocrinol Metab. 2002;  87 569-574
• 31 Franks S. Polycystic ovary syndrome.  N Engl J Med. 1995;  333 853-861
• 32 Geisthovel F, Frorath B, Brabant G. Acarbose reduces elevated testosterone serum concentration in hyperinsulinaemic premenopausal women: a pilot study.  Hum Reprod. 1996;  11 2377-2381
• 33 Ghazeeri G, Kutteh W H, Bryer-Ash M, Haas D, Ke R W. Effect of rosiglitazone on spontaneous and clomiphene citrat induced ovulation in women with polycystic ovary syndrome.  Fertil Steril. 2003;  79 562-566
• 34 Glueck C J, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformin-induced resumption of normal menses in 39 of 43 (91 %) previously amenorrhoic women with polycystic ovary syndrome.  Metabolism. 1999;  48 511-519
• 35 Hasegawa I, Murakawa H, Suzuki M, Yamamoto Y, Kurabayashi T, Tanaka K. Effect of troglitazone on endocrine and ovulatory performance in women with polycystic ovary syndrome.  Fertil Steril. 1999;  71 323-327
• 36 Hauner H. The mode of action of thiazolidinediones.  Diabetes Metab Res Rev. 2002;  18 10-15
• 37 Huber-Buchholz M M, Carey D G, Norman R J. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone.  J Clin Endocrinol Metab. 1999;  84 1470-1474
• 38 Ibanez L, Valls C, Ferrer A, Marcos M V, Rodriguez-Hierro F, de Zegher F. Sensitization to insulin induces ovulation in nonobese adolescents with anovulatory hyperandrogenism.  J Clin Endocrinol Metab. 2001;  86 3595-3598
• 39 Inzucchi S E, Maggs D G, Spollett G R, Page S L, Rife F S, Walton V, Shulman G. Efficiency and metabolic effects of metformin and troglitazone in type II diabetes mellitus.  N Engl J Med. 1998;  338 867-872
• 40 Iuorno M J, Jakubowicz D J, Dillon P, Gunn R, Allan G, Nestler J E. Effects of d-chiro-inositol in the polycystic ovary syndrome.  Endocr Pract. 2002;  8 417-423
• 41 Johnson J A, Majumdar S R, Simpson S H, Toth E L. Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes.  Diabetes Care. 2002;  25 2244-2248
• 42 Knochenhauer E S, Key T J, Kahsar-Miller M, Waggoner W, Boots L R, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospectve study.  J Clin Endocrinol Metab. 1998;  83 3078-3082
• 43 Knowler W C, Barrett-Connor E, Fowler S E, Hamman R F, Lachin J M, Walker E A, Nathan D M. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.  N Engl J Med. 2002;  346 393-403
• 44 Kocak M, Caliskan E, Simsir C, Haberal A. Metformin therapy improves ovulatory rates, cervical score and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome.  Fertil Steril. 2002;  77 101-106
• 45 Kolodziejczyk B, Duleba A J, Spaczynski R Z, Pawelczyk L. Metformin therapy improves hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome.  Fertil Steril. 2000;  73 1149-1154
• 46 Legro R S, Kunselman A R, Dodson W C, Dunaif A. 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. 1999;  84 165-169
• 47 Legro R S, Kunselman A R, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome.  Am J Med. 2001;  111 607-613
• 48 Legro R S, Strauss J F. Molecular progress in infertility: polycystic ovary syndrome.  Fertil Steril. 2002;  78 569-576
• 49 Lord J M, Flight I CH, Norman R J. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome.  Cochrane Databases Syst Rev. 2003;  3 CD003053
• 50 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
• 51 Mitwally M F, Kuscu N K, Yalcinkaya T M. High ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome.  Hum Reprod. 1999;  14 2700-2703
• 52 Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, Zanolini E, Muggeo M. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double blind, placebo-controlled six-month trial followed by open, long-term clinical evaluation.  J Clin Endocrinol Metab. 2000;  85 139-146
• 53 Morin-Papunen L C, Koivunen R M, Roukonen A, Martikainen H K. Metformin therapy improves menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome.  Fertil Steril. 1998;  69 691-696
• 54 Morin-Papunen L C, Vauhkonen I, Koivunen R M, Ruokonen A, Martikainen H K, Tapanainen J S. Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproteron acetate in obese women with polycystic ovary syndrome: a randomized study.  J Clin Endocrin Metab. 2000;  85 3161-3168
• 55 Nestler J E, Jakubowicz D J, Evans W S, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome.  N Engl J Med. 1998;  338 1876-1880
• 56 Ng E H, Wat N M, Ho P C. Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene-resistant polycystic ovaries: a randomized, double-blinded placebo-controlled trial.  Hum Reprod. 2001;  16 1625-1631
• 57 Nolan J, Ludvik B, Beerdsen P, Joyce M, Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subject treated with troglitazone.  N Engl J Med. 1994;  331 1188-1193
• 58 Norman R J, Masters L, Milner C R, Wang J X, Davies M J. Relative risk of conversion from normoglycaemia to impaired glucose tolerance or non-insulin dependent diabetes mellitus in polycystic ovarian syndrome.  Hum Reprod. 2001;  16 1995-1998
• 59 Paradisi G, Steinberg H O, Hempfling A, Cronin J, Hook G, Shepard M K, Baron A D. Polycystic ovary syndrome is associated with endothelial dysfunction.  Circulation. 2001;  3 1410-1415
• 60 Peppard H R, Marfori J, Iuorno M J, Nestler J E. Prevalence of polycystic ovary syndrome among premenopausalen women with type 2 diabetes.  Diabetes Care. 2001;  24 1050-1052
• 61 Pierpoint T, McKeigue P M, Isaacs A J, Wild S H, Jacobs H S. Mortality of women with polycystic ovary syndrome at long-term follow-up.  J Clin Epidemiol. 1998;  51 581-586
• 62 Pirwany I R, Yates R WS, Cameron I T, Fleming R. Effects of the insulin sensitizing drug metformin on ovarian function, follicular growth and ovulation rate in obese women with oligomenorrhoea.  Hum Reprod. 1999;  14 2963-2968
• 63 Reaven G M. Role of insulin resistance in human disease.  Diabetes. 1988;  37 1595-1607
• 64 Reaven G M. Insulin resistance, hyperinsulinemia, hypertriglyceridemia and hypertension. Parallels between human disease and rodent models.  Diabetes Care. 1991;  14 195-202
• 65 Romualdi D, Guido M, Ciampelli M, Giuliani M, Leoni F, Perri C, Lanzone A. Selctive effects of pioglitazone on insulin and androgen abnormalities in normo- and hyperinsulinaemic obese patients with polycystic ovary syndrome.  Hum Reprod. 2003;  18 1210-1218
• 66 Schachter M, Raziel A, Friedler S, Strassburger D, Bern O, Ron E L. Insulin resistance in patients with polycystic ovary syndrom is associated with elevated plasma homocysteine.  Hum Reprod. 2003;  18 721-727
• 67 Shobokshi A, Shaarawy M. Correction of insulin resistance and hyper-androgenism in polycystic ovary syndrome by combined rosiglitazone and clomiphene citrate therapy.  J Soc Gynecol Investig. 2003;  10 99-104
• 68 Stadtmauer L A, Toma S K, Riehl R M, Talbert L M. Metformin treatment of patients with polycystic ovary syndrome undergoing in vitro fertilization improves outcome and is associated with modulation of the insulin-growth factors.  Fertil Steril. 2001;  75 505-509
• 69 Stadtmauer L A, Toma S K, Riehl R M, Talbert L M. Impact of metformin therapy on ovarian stimulation and outcome in “coasted” patients with polycystic ovary syndrom undergoing in-vitro fertilization.  Reprod Biomed Online. 2002;  5 112-116
• 70 Talbott E, Clerici A, Berga S L, Kuller L, Guzick D, Detre K, Daniels T, Engberg R A. Adverse lipid and coronary heart disease risk profiles in young women with polycystic ovary syndrome: results of a case-control study.  J Clin Epidemiol. 1998;  51 415-422
• 71 Talbott E, Guzieck D, Clerici A, Berga S, Detre K, Weimar K, Kuller L. Coronary heart disease risk factors in women with polycystic ovary syndrome.  Arterioscler Thromb Vasc Biol. 1995;  15 821-826
• 72 Talbott E O, Guzieck D S, Suton-Tyrrell K, McHugh-Pemu K P, Zborowski J V, Remsberg K E, Kuller L H. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women.  Arterioscler Thromb Vasc Biol. 2000;  20 2414-2421
• 73 Tuomilehto J, Lindstrom J, Eriksson J G, Valle T T, Hamalainen H, Ilanne-Parrika P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rasta M, Salminen V, Uusitupa M. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance.  N Engl J Med. 2001;  344 1343-1350
• 74 Urbanek M, Legro R S, Driscoll D A, Azziz R, Ehrmann D A, Norman R J, Strauss J F, Spielman R S, Dunaif A. Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin.  Proc Natl Acad Sci. 1999;  96 8573-8578
• 75 Vandermolen D T, Ratts V S, Evans W S, Stovall D W, Kauma S W, Nestler J E. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone.  Fertil Steril. 2001;  75 310-315
• 76 Velazquez E M, Mendoza S, Hamer T, Sosa F, Glueck C J. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy.  Metabolism. 1994;  43 647-654
• 77 Velazquez E, Costa A, Mendoza S G. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome.  Obstet Gynecol. 1997;  90 392-395
• 78 Vribikova J, Bicikova M, Tallova J, Hill M, Starka L. Homocysteine and steriods levels in metformin treated women with polycystic ovary syndrome.  Exp Clin Endocrinol Diabetes. 2002;  110 74-76
• 79 Waterworth D M, Bennett S T, Gharani N, McCarthy M I, Hague S, Batty S, Conway G S, White D, Todd J A, Franks S, Williamson R. Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome.  Lancet. 1997;  349 1771-1772
• 80 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
• 81 Wild R A. Polycystic ovary syndrome: a risk for coronary artery disease?.  Am J Obstet Gynecol. 2002;  186 35-43
• 82 Wild R A. Long-term health consequences of PCOS.  Hum Reprod. 2002;  8 231-241
• 83 Zheng Z, Li M, Lin Y, Ma Y. Effect of rosiglitazone on insulin resistance and hyperandrogenism in polycystic ovary syndrome.  Zhonghua Fu Chan Ke Za Zhi. 2002;  37 271-273