Metformintherapie bei polyzystischem Ovarsyndrom (PCOS)

Zusammenfassung

Das polyzystische Ovarsyndrom (PCOS) ist eine der häufigsten Ursachen für die weibliche Infertilität. Neben den typischen Symptomen wie Oligo-/Amenorrhö, Hyperandrogenämie und Adipositas werden auch periphere Insulinresistenz, gestörte Glukosetoleranz und Hyperlipidämie beobachtet. Die Hyperinsulinämie und Veränderungen im IGF/IGFBP-System (insulin-like growth factor/insulin-like growth factor binding protein) spielen in der Pathogenese des PCOS vermutlich eine wichtige Rolle. Insulin und IGF bewirken eine Stimulation der ovariellen Androgenproduktion.

Vor diesem pathogenetischen Hintergrund erscheint eine Behandlung des PCOS durch Verbesserung der metabolischen Situation durch orale Antidiabetika wie z. B. Metformin sinnvoll: Metformin erhöht die Insulinempfindlichkeit, reduziert aber auch die Glukoseaufnahme aus dem Darm und ebenso die hepatische Glukoneogenese. Beim PCOS bewirkt Metformin eine Zyklusregulierung mit deutlicher Steigerung der Ovulationsrate sowie eine Gewichtsreduktion bei meistens adipösen PCOS-Patientinnen. Des Weiteren kommt es unter der Therapie zu einer Reduktion des Testosteronspiegels und Besserung der Akne sowie des Hirsutismus. Im Rahmen der Sterilitätstherapie zeigt sich ein besseres Ansprechen auf die Clomiphen- und FSH-Stimulation mit einer Erhöhung der Schwangerschaftsraten. Erste Studien zeigen auch einen positiven Effekt in der Frühschwangerschaft mit einer Reduktion der Fehlgeburtenrate, wobei es hier noch weiterer Untersuchungen bedarf. Die Metformineinnahme sollte in der Therapie des PCOS über mindestens 3 Monate erfolgen. Die Dosierung beträgt 3 × 500 mg, bzw. 2 × 850 mg. Prinzipiell ist die Metformintherapie bei adipösen PCOS-Patientinnen mit abdominalem Fettverteilungsmuster und peripherer Insulinresistenz indiziert, wobei auch die schlanken PCOS-Patientinnen von der Therapie profitieren können.

Abstract

The polycystic ovary syndrome (PCOS) is a common reason for female subfertility. Apart from the cardinal symptoms of irregular menstrual bleeding, hyperandrogenism and obesity, many women with PCOS have insulin resistance, impaired glucose tolerance and hyperlipidemia. Hyperinsulinemia and changes in insulin-like growth factor (IGF) and its binding protein appear to be central in the pathogenesis of PCOS. Both insulin and IGF indirectly stimulate ovarian synthesis of androgens. This suggests using antidiabetic agents to treat women with PCOS. Metformin increases insulin sensitivity, reduces glucose uptake and inhibits hepatic glucose synthesis. In obese women metformin promotes weight loss, improves menstrual control and increases ovuation rates. With metformin treatment, testosterone levels decrease and acne and hirsism improve. For ovarian stimulation, metformin improves the response to clomiphene or FSH, with increased pregancy rates. Some studies suggest reduced rates of pregnancy loss with metformin in early pregnancy. Metformin seems appropriate particularly for obese PCOS patients with peripheral insulin resistance. The recommended dosage is 500 mg tid or 850 mg bid for at least 3 months.

PCOS - Hyperandrogenämie - IGF - Hyperinsulinämie - Metformin - Sterilitätstherapie

PCOS - hyperandrogenemia - IGF - hyperinsulinemia - metformin infertility

Literatur

• 1 Adams J. et al . Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin releasing hormone.  Lancet. 1985;  2 1375-1379
• 2 Azziz R. et al . 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
• 3 Balen A. . Homburg R (ed) Polycystic Ovary Syndrome. Martin Dunitz 2001: 19-27
• 4 Barbieri R L. et al . The role of hyperinsulinemia in pathogenesis of ovarian hyperandrogenism.  Fertil Steril. 1988;  50 197-212
• 5 Barbieri R L. Induction of ovulation in infertile women with hyperandrogenism and insulin resistance.  Am J Obstet Gynecol. 2000;  183 412-1418
• 6 Burghen G A. et al . Correlation of hyperandrogenism with hyperinsulinism in polycystic ovary disease.  J Clin Endocrinol Metab. 1980;  50 113-116
• 7 Clark A M. et al . Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment.  Hum Reprod. 1988;  13 1502-1505
• 8 Coetzee E J, Jackson W P. Oral hypoglycaemics in the first trimester and fetal outcome.  S Afr Med J. 1984;  65 635-637
• 9 De Leo. et al . Effects of metformin on gonadotropin-induces ovulation in women with polycystic ovary syndrome.  Fertil Steril. 1999;  72 282-285
• 10 De Leo. et al . Effect of metformin on insulin-like growth factor (IGF) 1 and IGF-binding protein 1 in polycystic ovary syndrome.  J Clin Endocrinol Metab. 2000;  85 1598-1600
• 11 Diamanti-Kandarakis E. et al . Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome.  Eur J Endocrinol. 1998;  138 269-274
• 12 Dunaif A. et al . Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome.  Diabetes. 1992;  41 1257-1266
• 13 Dunaif A. et al . Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle: a potential mechanism for insulin resistance in the polycystic ovary syndrome.  J Clin Invest. 1995;  96 801-810
• 14 Dunaif A. et al .Polycystic Ovary Syndrom (Current Issues in Endocrinology and Metabolism). 1st ed. Boston; Blackwell Scientific 1992
• 15 Dunaif A. et al . β-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome.  J Clin Endocrinol Metab. 1996;  81 942-947
• 16 Ehrmann D A. et al . Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome.  Diabetes Care. 1999;  22 141-146
• 17 Ehrmann D A. et al . Effect of metformin on insulin secretion, insulin action and ovarian steroidogenesis in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 1997;  82 524-530
• 18 Ehrmann D A. et al . Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and familiy history of non-insulin-dependent diabetes mellitus.  J Clin Invest. 1995;  96 520-527
• 19 Fleming R. et al . Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in randomized double-blind placebo-controlled trial.  J Clin Endocrinol Metab. 2002;  87 569-574
• 20 Geisthövel F. Funktioneller Hyperandrogenismus (sog. „Syndrom polyzystischer Ovarien“).  Gynäkologe. 2002;  35 48-63
• 21 Gharani N. et al . Association of the steroid synthesis gene CYP11a with polycystic ovary syndrom and hyperandrogenism.  Hum Mol Genet. 1997;  6 397-402
• 22 Gjonnaess H. Late endocrine effects of ovarian electrocautery in women with polycystic ovary syndrome.  Fertil Steril. 1998;  69 697-701
• 23 Glueck C J. et al . Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study.  Fertil Steril. 2001;  75 46-52
• 24 Glueck C J. et al . Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome.  Fertil Steril. 2002;  77 520-525
• 25 Glueck C J. et al . Metformin-induced resumption of normal menses in 39 of 43 (91 %) previously amenorrheic women with the polycystic ovary syndrome.  Metabolism. 1999;  48 511-519
• 26 Glueck C J. et al . Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin.  Hum Reprod. 2002;  17 2858-2864
• 27 Hasegawa I. et al . Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome.  Fertil Steril. 1999;  71 323-327
• 28 Horton R. et al . Androgen induction of steroid 5 alpha-reductase may be mediated via insulin-like growth factor-1.  Endocrinol. 1993;  133 447-451
• 29 Jakubowicz D J. et al . Effects of metformin on early pregnancy loss in the polycystic ovary syndrome.  J Clin Endocrinol Metab. 2002;  87 524-529
• 30 Keck C, Geisthövel F. Long-term FSH-Therapie zur Behandlung der Sterilität beim „hypersensitiven“ Ovar.  Geburtsh Frauenheilk. 1999;  59 215-219
• 31 Kocak M. et al . Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome.  Fertil Steril. 2002;  77 101-106
• 32 Kolodziejczyk B. et al . Metformin decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome.  Fertil Steril. 2000;  73 1149-1154
• 33 La Marca A. et al . Metformin treatment reduces ovarian cytochrome P-450 c17alpha response to human chorionic gonadotropin in women with insulin resistance-related polycystic ovary syndrome.  Hum Reprod. 2000;  15 21-23
• 34 La Marca A. et al . Effects of metformin an adrenal steroidgenesis in women with polycystic ovary syndrome.  Fertil Steril. 1999;  72 985-989
• 35 Legro R S. et al . Prevalence and predictors of risk for Type 2 Diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrom: a prospective, controlled study in 254 affected women.  J Clin Endocrinol Metab. 1999;  84 165-169
• 36 Legro R S, Strauss J F. Molecular progress in infertility: polycystic ovary syndrom.  Fertil Steril. 2002;  78 569-576
• 37 Legro R S. Polycystic ovary syndrom-long term sequelae and management.  Minerva Ginecologica. 2002;  54 97-114
• 38 Leidenberger F A. Klinische Endokrinologie für Frauenärzte. 2. Aufl. Springer-Verlag 1998
• 39 Mikola M. et al . Obstetric outcome in women with polycystic ovarian syndrome.  Hum Reprod. 2001;  16 226-229
• 40 Moghetti P. et al . Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomised, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation.  J Clin Endocrin Metab. 2000;  85 139-146
• 41 Morin-Papunem L C. et al . 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
• 42 Morin-Papunem L C. et al . Metformin Therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome.  Fertil Steril. 1998;  69 691-696
• 43 Morin-Papunem L C. et al . Decreased serum leptin concentration during metformin therapie in obese women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 1998;  83 2566-2568
• 44 Nardo L G. et al . Metformin therapy in the management of polycystic ovary syndrome: endocrine, metabolic and reproductive effects.  Gynecol Endocrinol. 2001;  15 373-380
• 45 Nestler J E. et al . Effects of metformin on spontaneus and clomiphen-induces ovulation in the polycystic ovary syndrome.  New Eng J Med. 1998;  338 1876-1880
• 46 Nestler J E. et al . Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome.  N Engl J Med. 1999;  340 1314-1320
• 47 Nestler J E. et al . Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome.  Fertil Steril. 2002;  77 209-215
• 48 Nestler J E. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17α activity and serum androgens.  J Clin Endocrinol Metab. 1997;  82 475-479
• 49 Nestler J E. Letters to the Editor.  Fertil Steril. 2002;  78 654
• 50 Pasquali R. et al . 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. 2000;  85 2767-2774
• 51 Schweiger U. et al . Das Syndrom der polyzystischen Ovarien.  Gynäkologe. 2002;  35 36-40
• 52 Seelig A S. Intraovarielles Insulin-like Growth Faktor-System. Bedeutung beim polyzystischen Ovarsyndrom.  Gynäkologe. 2002;  35 41-47
• 53 Seli E, Duleba A J. Should patients with polycystic ovary syndrome be treated with metformin? Proven and potential benefits.  Hum Reprod. 2002;  17 2230-2236
• 54 Sills E S. et al . Correction of hyperinsulinemia in oligoovulatory women with clomiphene-resistant polycystic ovary syndrome: a review of therapeutic rationale and reproductive outcomes.  Eur J Obst Gynecol. 2000;  91 135-141
• 55 Stadtmauer L A. et al . Metformin treatment of patients with polycystic ovary syndrome undergoing in vitro fertilisation improves outcome and is associated with modulation of the insulin-like growth factors.  Fertil Steril. 2001;  75 505-509
• 56 Urbanek M. et al . Thirty-seven candidate genes for polycystic ovary syndrom: strongest evidence for linkage is with follistatin.  Proc Natl Acad Sci USA. 1999;  96 8573-8578
• 57 Vandermolen D T. et al . Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citarte alone.  Fertil Steril. 2001;  75 310-315
• 58 Velasquez E M. et al . Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein (a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome.  Metabolism. 1997;  46 454-457
• 59 Velazquez E M. et al . Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenaemia, and systolic blood pressure while facilitating normal menses and pregnancy.  Metab Clin Ep. 1994;  43 647-654
• 60 Waterworth D M. et al . Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrom.  Lancet. 1997;  349 986-990
• 61 Weiss J M. et al . Das Karzinomrisiko von Frauen mit Syndrom der polyzystischen Ovarien (PCOS).  Gynäkologe. 2002;  35 31-35
• 62 Wild S. et al . Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study.  Clin Endocrinol. 2000;  52 595-600
• 63 Zhang L H. et al . Serine phosphorylation of human P450c17 increases 17, 20-lyase activity: implications for adrenarche and the polycystic ovary syndrome.  Proc Natl Acad Sci USA. 1995;  92 10619-10623