Hyperandrogenämie - Teil 2

Mögliche Ansätze zur Therapie der Hyperandrogenämie sind in Tab. [1] dargestellt. Daneben existieren kosmetische Maßnahmen, die vom Bleichen der störenden Haare über die Epilation mit elektrischen Geräten oder Wachsplatten bzw. Rasur bis zur Lasertherapie reichen. Für diese Alternativen kann unter Umständen bei den Krankenkassen eine Kostenübernahme erwirkt werden.

Tab. 1 Angriffspunkte bei der Therapie der Hyperandrogenämie Produktion Kortikosteroide (ACTH-Suppression →, wingdings Suppression der Nebennierenrindenfunktion) orale Kontrazeptiva (LH/FSH-Suppression →, wingdings Suppression der Ovarfunktion) Metformin/Glitazone (Senkung der Hyperinsulinämie bzw. Insulinsensitizer →, wingdings Korrektur des verschobenen LH/FSH-Quotienten und Minderung der Androgensynthese in Ovar und Nebennierenrinde durch direkte Wirkung?) Transport orale Kontrazeptiva (SHBG-Erhöhung →, wingdings Senkung der freien Androgene) Wirkung 5α-Reduktase (Hemmung der Konversion von Testosteron zu Dihydrotestosteron) Finasterid (selektive Hemmung der 5α-Reduktase Typ 2) Dutasterid (Hemmung der 5α-Reduktase Typ 1 + 2) Spironolacton (Aldosteronantagonist, Androgenrezeptorblocker) Flutamid (Antiandrogen) Antiandrogenwirksame Gestagene (Rezeptorblockade) Cyproteronacetat (relative Wirksamkeit: 1,0) Dienogest (relative Wirksamkeit: 0,4) Drospirenon (relative Wirksamkeit: 0,3) Chlormadinonacetat (relative Wirksamkeit: 0,2)

Ein Entscheidungsbaum zur Wahl des richtigen therapeutischen Weges ist in Abb. [1] dargestellt. Dieses Schema macht deutlich, dass im Fall der vorwiegend kosmetischen Problematik ein orales Kontrazeptivum mit primär antiandrogen wirksamem Gestagen die Therapie der ersten Wahl darstellt gefolgt von alternativen Ansätzen wie Spironolacton, Flutamid und Finasterid. Eine Ausnahme bildet die PCOS-Patientin mit nachweisbarer peripherer Insulinresistenz, bei der sowohl im Rahmen der Kosmetik als auch bei unerfülltem Kinderwunsch Metformin eine nachgewiesen hoch aktive Therapie darstellt.

Abb. 1 Entscheidungsbaum zur Therapiefindung bei Hyperandrogenämie bzw. Hyperandrogenismus.

Dexamethason wird bei der hyperandrogenämischen Kinderwunschpatientin eingesetzt. Diese Therapie ist nur in Ausnahmefällen (s. u.) effektiv und erfordert stets die Kombination mit einem Insulinsensitizer oder einer ovariellen Stimulation mit z. B. Clomifen.

Literatur

• 1 Geisthövel F. Funktioneller Hyperandrogenismus (sog. „Syndrom polyzystischer Ovarien“).  Gynäkologe. 2002;  35 48-63
• 2 Fassnacht M, Schlenz N, Schneider S B, Wudy S A, Allolio B, Arlt W. Beyond adrenal and ovarian androgen generation: Increased peripheral 5 alpha-reductase activity in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2003;  88 2760-2766
• 3 Speiser P W, White P C. Congenital adrenal hyperplasia.  N Engl J Med. 2003;  349 776-788
• 4 Dörr H G, Sippell W G. Prenatal dexamethasone treatment in pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: effect on midgestational amniotic fluid steroid levels.  J Clin Endocrinol Metab. 1993;  76 117-120
• 5 Joint LWPES/ESPE CAH Working Group . Consensus Statement on 21-Hydroxylase Deficiency from The Lawson Wilkins Pediatric Endocrine Society and The European Society for Paediatric Endocrinology.  J Clin Endocrinol Metab. 2002;  87 4048-4053
• 6 New M I, Carlson A, Obeid J. et al . Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies.  J Clin Endocrinol Metab. 2001;  86 5661-5667
• 7 Meyer-Bahlburg H F, Dolezahl C, Baker S W, Carlson D, New M I. Cognitive and motor development of children with and without congenital adrenal hyperplasia after early-prenatal dexamethasone.  J Clin Endocrinol Metab. 2004;  89 610-614
• 8 Zawadski J K, Dunaif A. Diagnostic criteria for polycystic ovarian syndrome: towards a rationale approach. Dunaif A, Givens JR, Haseltine F Polycystic Ovary Syndrome. (1st ed). Boston; Blackwell Scientific 1992: 377-384
• 9 Pierroz D D, Aebi A C, Huhtaniemi I T, Aubert M L. Many LH peaks are needed to physiologically stimulate testosterone secretion: modulation by fasting and NPY.  Am J Physiol. 1999;  276 E603-E610
• 10 Hileman S M, Lubbers L S, Kuehl D E, Schaeffer D J, Rhodes L, Jackson G L. Effect of inhibiting 5 alpha-reductase activity on the ability of testosterone to inhibit luteinizing hormone release in male sheep.  Biol Reprod. 1994;  50 1244-1250
• 11 Belgorosky A, Chahin S, Rivarola M A. Elevation of serum luteinizing hormone levels during hydrocortisone treatment in infant girls with 21-hydroxylase deficiency.  Acta Paediatr. 1996;  85 1172-1175
• 12 Patel K, Coffler M S, Dahan M H. et al . Increased luteinizing hormone secretion in women with polycystic ovary syndrome is unaltered by prolonged insulin infusion.  J Clin Endocrinol Metab. 2003;  88 5456-5461
• 13 Weiss J M, Polack S, Diedrich K, Ortmann O. Effects of insulin on luteinizing hormone and prolactin secretion and calcium signaling in female rat pituitary cells.  Arch Gynecol Obstet. 2003;  269 45-50
• 14 Adams J, Frank S, Polson D W, Abdulwahid N. et al . Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin releasing hormone.  Lancet. 1985;  2 1375-1379
• 15 Revised consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.  Fertil Steril. 2004;  81 19-25
• 16 Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS).  Hum Reprod. 2004;  19 41-47
• 17 Nahum R, Thong K J, Hillier S G. Metabolic regulation of androgen production by human thecal cells in vitro.  Hum Reprod. 1995;  10 75-81
• 18 Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis.  Endocr Rev. 1997;  18 774-800
• 19 Poretsky L, Kalin M F. The gonadotropic function of insulin.  Endocr Rev. 1987;  8 132-141
• 20 Xia Y X, Weiss J M, Polack S, Diedrich K, Ortmann O. Interactions of insulin-like growth factor-I, insulin and estradiol with GnRH-stimulated luteinizing hormone release from female rat gonadotrophs.  Eur J Endocrinol. 2001;  144 73-79
• 21 King H, Rewers M. Global estimates for prevalence of diabetes mellitus and impaired glucose tolerance in adults. WHO Ad Hoc Diabetes Reporting Group.  Diabetes Care. 1993;  16 157-177
• 22 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
• 23 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
• 24 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
• 25 Peppard H R, Marfori J, Iuorno M J, Nestler J E. Prevalence of polycystic ovary syndrome among premenopausal women with type 2 diabetes.  Diabetes Care. 2001;  24 1050-1052
• 26 Conn J J, Jacobs H S, Conway G S. The prevalence of polycystic ovaries in women with type 2 diabetes mellitus.  Clin Endocrinol (Oxf). 2000;  52 81-86
• 27 Solomon C G, Hu F B, Dunaif A. et al . Long or highly irregular menstrual cycles as a marker for risk of type 2 diabetes mellitus.  Jama. 2001;  286 2421-2426
• 28 Colilla S, Cox N J, Ehrmann D A. Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their first degree relatives.  J Clin Endocrinol Metab. 2001;  86 2027-2031
• 29 Dunaif A, Segal K R, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome.  Diabetes. 1989;  38 1165-1174
• 30 Dunaif A, Segal K R, Shelley D R, Green G, Dobrjansky A, Licholai T. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome.  Diabetes. 1992;  41 1257-1266
• 31 Dunaif A, Xia J, Book C B, Schenker E, Tang Z. 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
• 32 Dunaif A, Finegood D T. Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome.  J Clin Endocrinol Metab. 1996;  81 942-947
• 33 Ehrmann D A, Sturis J, Byrne M M, Karrison T, Rosenfield R L, Polonsky K S. Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus.  J Clin Invest. 1995;  96 520-527
• 34 O'Meara N M, Blackman J D, Ehrmann D A. et al . Defects in beta-cell function in functional ovarian hyperandrogenism.  J Clin Endocrinol Metab. 1993;  76 1241-1247
• 35 Book C B, Dunaif A. Selective insulin resistance in the polycystic ovary syndrome.  J Clin Endocrinol Metab. 1999;  84 3110-3116
• 36 Bjercke S, Dale P O, Tanbo T, Storeng R, Ertzeid G, Abyholm T. Impact of insulin resistance on pregnancy complications and outcome in women with polycystic ovary syndrome.  Gynecol Obstet Invest. 2002;  54 94-98
• 37 Kannel W B, D'Agostino R B, Wilson P W, Belanger A J, Gagnon D R. Diabetes, fibrinogen, and risk of cardiovascular disease: the Framingham experience.  Am Heart J. 1990;  120 672-676
• 38 Wild R A. Obesity, lipids, cardiovascular risk, and androgen excess.  Am J Med. 1995;  98 27S-32S
• 39 Wild S, Pierpoint T, McKeigue P, Jacobs H. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study.  Clin Endocrinol (Oxf). 2000;  52 595-600
• 40 Amowitz L L, Sobel B E. Cardiovascular consequences of polycystic ovary syndrome.  Endocrinol Metab Clin North Am. 1999;  28 439-458 viii
• 41 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
• 42 Paradisi G, Steinberg H O, Hempfling A. et al . Polycystic ovary syndrome is associated with endothelial dysfunction.  Circulation. 2001;  103 1410-1415
• 43 Talbott E, Guzick D, Clerici A. et al . Coronary heart disease risk factors in women with polycystic ovary syndrome.  Arterioscler Thromb Vasc Biol. 1995;  15 821-826
• 44 Talbott E O, Guzick D S, Sutton-Tyrrell K. et al . Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women.  Arterioscler Thromb Vasc Biol. 2000;  20 2414-2421
• 45 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
• 46 Solomon C G, Hu F B, Dunaif A. et al . Menstrual cycle irregularity and risk for future cardiovascular disease.  J Clin Endocrinol Metab. 2002;  87 2013-2017
• 47 Hiort O, Holterhus P M, Nitsche E M. Physiology and pathophysiology of androgen action.  Baillieres Clin Endocrinol Metab. 1998;  12 115-132
• 48 Diamanti-Kandarakis E, Baillargeon J P, Iuorno M J, Jakubowicz D J, Nestler J E. A modern medical quandary: polycystic ovary syndrome, insulin resistance, and oral contraceptive pills.  J Clin Endocrinol Metab. 2003;  88 1927-1932
• 49 Hammerstein J, Meckies J, Leo-Rossberg I, Moltz L, Zielske F. Use of cyproterone acetate (CPA) in the treatment of acne, hirsutism and virilism.  J Steroid Biochem. 1975;  6 827-836
• 50 Leo-Rossberg I, Laur S, Zielske F, Hammerstein J. Reversed sequential therapy of hirsutism using cyproterone acetate. I. Further clinical observations.  Acta Endocrinol Suppl (Copenh). 1971;  152 14
• 51 Zielske F, Dreykluft R, Magnus U, Hammerstein J. Reversed sequential therapy of hirsutism using cyproterone acetate. II. Hormonal analyses.  Acta Endocrinol Suppl (Copenh). 1971;  152 15
• 52 Azziz R, Black V Y, Knochenhauer E S, Hines G A, Boots L R. Ovulation after glucocorticoid suppression of adrenal androgens in the polycystic ovary syndrome is not predicted by the basal dehydroepiandrosterone sulfate level.  J Clin Endocrinol Metab. 1999;  84 946-950
• 53 Imani B, Eijkemans M J, Te Velde E R, Habbema J D, Fauser B C. Predictors of chances to conceive in ovulatory patients during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility.  J Clin Endocrinol Metab. 1999;  84 1617-1622
• 54 Eijkemans M J, Imani B, Mulders A G, Habbema J D, Fauser B C. High singleton live birth rate following classical ovulation induction in normogonadotrophic anovulatory infertility (WHO 2).  Hum Reprod. 2003;  18 2357-2362
• 55 van Santbrink E J, Fauser B C. Urinary follicle-stimulating hormone for normogonadotropic clomiphene-resistant anovulatory infertility: prospective, randomized comparison between low dose step-up and step-down dose regimens.  J Clin Endocrinol Metab. 1997;  82 3597-3602
• 56 van Santbrink E J, Donderwinkel P F, van Dessel T J, Fauser B C. Gonadotrophin induction of ovulation using a step-down dose regimen: single-centre clinical experience in 82 patients.  Hum Reprod. 1995;  10 1048-1053
• 57 Venturoli S, Marescalchi O, Colombo F M. et al . A prospective randomized trial comparing low dose flutamide, finasteride, ketoconazole, and cyproterone acetate-estrogen regimens in the treatment of hirsutism.  J Clin Endocrinol Metab. 1999;  84 1304-1310
• 58 Carmina E, Lobo R A. Treatment of hyperandrogenic alopecia in women.  Fertil Steril. 2003;  79 91-95
• 59 Carmina E, Lobo R A. A comparison of the relative efficacy of antiandrogens for the treatment of acne in hyperandrogenic women.  Clin Endocrinol (Oxf). 2002;  57 231-234
• 60 Muderris I I, Bayram F, Guven M. A prospective, randomized trial comparing flutamide (250 mg/d) and finasteride (5 mg/d) in the treatment of hirsutism.  Fertil Steril. 2000;  73 984-987
• 61 Fruzzetti F, Bersi C, Parrini D, Ricci C, Genazzani A R. Treatment of hirsutism: comparisons between different antiandrogens with central and peripheral effects.  Fertil Steril. 1999;  71 445-451
• 62 Salpeter S R, Greyber E, Pasternak G A, Salpeter E E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis.  Arch Intern Med. 2003;  163 2594-2602
• 63 Haas D A, Carr B R, Attia G R. Effects of metformin on body mass index, menstrual cyclicity, and ovulation induction in women with polycystic ovary syndrome.  Fertil Steril. 2003;  79 469-481
• 64 Costello M F, Eden J A. A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome.  Fertil Steril. 2003;  79 1-13
• 65 Harborne L, Fleming R, Lyall H, Sattar N, Norman J. Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary syndrome.  J Clin Endocrinol Metab. 2003;  88 4116-4123
• 66 Lord J M, Flight I H, Norman R J. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome.  Cochrane Database Syst Rev. 2003;  CD003053
• 67 Coetzee E J, Jackson W P. Pregnancy in established non-insulin-dependent diabetics. A five-and-a-half year study at Groote Schuur Hospital. S. Afr.  Med J. 1980;  58 795-802
• 68 Coetzee E J, Jackson W P. Diabetes newly diagnosed during pregnancy: A 4-year study at Groote Schuur Hospital.  S Afr Med J. 1979;  56 467-475
• 69 Jakubowicz D J, Iuorno M J, Jakubowicz S, Roberts K A, Nestler J E. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome.  J Clin Endocrinol Metab. 2002;  87 524-529
• 70 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
• 71 Glueck C J, Wang P, Goldenberg N, Sieve-Smith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin.  Hum Reprod. 2002;  17 2858-2864
• 72 Glueck C J, Wang P, Kobayashi S, Phillips H, Sieve-Smith L. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome.  Fertil Steril. 2002;  77 520-525
• 73 Glueck C J, Phillips H, Cameron D, Sieve-Smith L, Wang P. 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
• 74 Cavaghan M K, Ehrmann D A, Byrne M M, Polonsky K S. Treatment with the oral antidiabetic agent troglitazone improves beta cell responses to glucose in subjects with impaired glucose tolerance.  J Clin Invest. 1997;  100 530-537
• 75 Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome.  J Clin Endocrinol Metab. 1996;  81 3299-3306
• 76 Ehrmann D A, Schneider D J, Sobel B E. et al . Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 1997;  82 2108-2116
• 77 Azziz R, Ehrmann D, Legro R S. 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
• 78 Cataldo N A, Abbasi F, McLaughlin T L, Lamendola C, Reaven G M. Improvement in insulin sensitivity followed by ovulation and pregnancy in a woman with polycystic ovary syndrome who was treated with rosiglitazone.  Fertil Steril. 2001;  76 1057-1059
• 79 Ghazeeri G, Kutteh W H, Bryer-Ash M, Haas D, Ke R W. Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome.  Fertil Steril. 2003;  79 562-566
• 80 Shobokshi A, Shaarawy M. Correction of insulin resistance and hyperandrogenism in polycystic ovary syndrome by combined rosiglitazone and clomiphene citrate therapy.  J Soc Gynecol Investig. 2003;  10 99-104
• 81 Glueck C J, Moreira A, Goldenberg N, Sieve L, Wang P. Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin.  Hum Reprod. 2003;  18 1618-1625
• 82 Nestler J E, Stovall D, Akhter N, Iuorno M J, Jakubowicz D J. Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome.  Fertil Steril. 2002;  77 209-215
• 83 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 2057-62
• 84 Nestler J E, Jakubowicz D J. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome.  N Engl J Med. 1996;  335 617-623
• 85 Nestler J E, Jakubowicz D J. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens.  J Clin Endocrinol Metab. 1997;  82 4075-4079
• 86 Velazquez E, Acosta A, Mendoza S G. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome.  Obstet Gynecol. 1997;  90 392-395
• 87 Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A. Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome.  Eur J Endocrinol. 1998;  138 269-274
• 88 Morin-Papunen L C, Koivunen R M, Ruokonen A, Martikainen H K. Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome.  Fertil Steril. 1998;  69 691-696
• 89 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
• 90 Glueck C J, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformin-induced resumption of normal menses in 39 of 43 (91 %) previously amenorrheic women with the polycystic ovary syndrome.  Metabolism. 1999;  48 511-519
• 91 La Marca A, Morgante G, Paglia T, Ciotta L, Cianci A, De L V. Effects of metformin on adrenal steroidogenesis in women with polycystic ovary syndrome.  Fertil Steril. 1999;  72 985-989
• 92 Pirwany I R, Yates R W, 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
• 93 Unluhizarci K, Kelestimur F, Bayram F, Sahin Y, Tutus A. The effects of metformin on insulin resistance and ovarian steroidogenesis in women with polycystic ovary syndrome.  Clin Endocrinol (Oxf). 1999;  51 231-236
• 94 Moghetti P, Castello R, Negri C. et al . 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. 2000;  85 139-146
• 95 Kolodziejczyk B, Duleba A J, Spaczynski R Z, Pawelczyk L. Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome.  Fertil Steril. 2000;  73 1149-1154
• 96 Pasquali R, Gambineri A, Biscotti D. 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
• 97 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
• 98 Baysal B, Batukan M, Batukan C. Biochemical and body weight changes with metformin in polycystic ovary syndrome.  Clin Exp Obstet Gynecol. 2001;  28 212-214
• 99 Vrbikova J, Hill M, Starka L, Vondra K. Prediction of the effect of metformin treatment in patients with polycystic ovary syndrome.  Gynecol Obstet Invest. 2002;  53 100-104
• 100 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
• 101 Karck U. Therapie der Hyperandrogenämie und ihrer Symptome Hirsutismus, Seborrhö und Akne.  Gynäkologe. 2002;  35 22-30
• 102 Azziz R. The evaluation and management of hirsutism.  Obstetrics & Gynecology. 2003;  101 995-1007
• 103 Lucky A W, Piacquadio D J, Ditre C M. et al . A randomized, placebo-controlled trial of 5 % and 2 % topical minoxidil solutions in the treatment of female pattern hair loss.  J Am Acad Dermatol. 2004;  50 541-553
• 104 Bouhanna P. Androgenetic alopecia: Combining medical and surgical treatments.  Dermatol Surg. 2003;  29) 1130-1134
• 105 Chen W C, Thiboutot D, Zouboulis C C. Cutaneous androgen metabolism: Basic research and clinical perspectives.  J Invest Dermatol. 2002;  119 992-1007
• 106 Hanneken S, Ritzmann A, Nöthen M M, Kruse R. Androgenetische Alopezie.  Hautarzt. 2003;  54 703-712
• 107 Hunter M H, Carek P J. Evaluation and treatment of hirsutism.  American Family Physician. 2003;  67 2565-2572
• 108 Price V H. Androgenetic alopecia in women.  J Invest Dermatol Symposium Proceedings. 2003;  8 24-27
• 109 Kaufmann K D. Androgens and alopecia.  Mol Cell Endocrinol. 2002;  198 89-95
• 110 Van der Spuy Z M, le Roux P A. Cyproterone acetate for hirsutism. (Cochrane Review). The Cochrane Library. Chichester, UK; John Wiley & Sons, Ltd. 2004 2: 1-53
• 111 Farquar C, Lee O, Toomath R, Jepson R. Spironolactone versus placebo or in combination with steroids for Hirsutism and/or acne. (Cochrane Review). The Cochrane Library. Chichester, UK; John Wiley & Sons, Ltd. 2004 2: 1-33
• 112 Lumchi F, Rondinone R. Use of cyproterone acetate, finasteride and spironolactone to treat idiopathic hirsurtism.  Fertil Steril. 2003;  79 942-946
• 113 Birch M P, Lalla S C, Messenger A G. Female pattern hair loss.  Clin Dermatol. 2002;  27 283-388
• 114 Fischer T W, Burmeister G, Schmidt H W, Elsner P. Melatonin increases anagen hair rate in women with androgenetic alopecia or diffuse alopecia: results of a pilot randomized controlled trial.  Br J Dermatol. 2004;  150 341-345
• 115 Raulin C, Greve B. Aktueller Stand der Photoepilation.  Hautarzt. 2000;  51 809-817
• 116 Trüeb R M. Neues und Bewährtes in der Therapie von Haarerkrankungen.  Hautarzt. 2003;  45 732-740
• 117 McPhaul M J. Factors that mediate and modulate androgen action.  J Invest Dermatol Symposium Proceedings. 2003;  8 1-5
• 118 Norwood O T. Incidence of female androgenetic alopecia (female pattern alopecia).  Dermatol Surg. 2001;  27 53-54
• 119 Javidnia K, Dastgheib L, Samani M S, Nasiri A. Antihirsutim activity of fennel (fruits of Foeniculum vulgare) extract. A double-blind placebo controlled study.  Phytomedicine. 2003;  10 455-458
• 120 Glueck C J, Goldenberg N, Wang P, Loftspring M, Sherman A. Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy.  Hum Reprod. 2004;  19 510-521
• 121 Elder A T, Hague W M, Davoren P M, Oliver J. et al . Contraindications to use of metformin.  BMJ. 2003;  326 762
• 122 National Collaborating Centre for Women's and Children's Health .Clinical Guideline. London; RCOG Press 2004: 1-216
• 123 Kunte C, Wolf H. Aktuelle Therapie der Hypertrichosen.  Hautarzt. 2001;  52 993-997
• 124 Wolf H. unveröffentlichte Daten, LMU München. 2004
• 125 Farquhar C, Vandekerckhove P, Lilford R. Laparoscopic “drilling” by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome.  The Cochrane Library. Oxford; Update Software 2002 3
• 126 El Saeed M, Ezzar M, Hasan M, Elhelw Aboumaaty B Z, Aboulghar M. High incidence of pelviv adhesions detected by secondary look laparoscopy after laparoscopic drilling.  Middle East Fert Soc J. 2000;  5 519-525
• 127 Farquhar C M, Williamson K, Brown P M, Garland J. An economic evaluation of laparoscopic ovarian diathermy versus gonadotrophin therapy for women with clomiphene citrate resistant polycystic ovary syndrome.  Hum Reprod. 2004;  19 1110-1115
• 128 Shapiro L, Pastuszak A, Curto G, Koren G. Safety of first trimester exposure to topical tretinoin (Letter).  Lancet. 1997;  350 1134-1144
• 129 Jick S S, Terris B Z, Jick H. First trimester topical tretinoin and congenital disorders.  Lancet. 1993;  341 1181-1182
• 130 Thomas L. Labor und Diagnose. 5. Aufl. Frankfurt/Main; TH-Books 1998