, Volume 63, Issue 5, pp 463–492 | Cite as

Progestogens with Antiandrogenic Properties

  • Daniel Raudrant
  • Thomas RabeEmail author
Review Article


Chlormadinone acetate, cyproterone acetate and dienogest are potent, orally active progestogens, which have antiandrogenic instead of partial androgenic activity. They act mainly by blocking androgen receptors in target organs, but also reduce the activity of skin 5α-reductase, the enzyme responsible for converting testosterone to the more potent androgen, 5α-dihydrotestosterone, in sebaceous glands and hair follicles. Chlormadinone acetate and cyproterone acetate also suppress gonadotropin secretion, thereby reducing ovarian and adrenal androgen production.

Combined oral contraceptives (COCs) containing antiandrogenic progestogens provide highly effective contraception (gross and adjusted Pearl indices: 0–0.7 and 0–0.3, respectively) with excellent cycle control. Furthermore, COCs containing 2mg of chlormadinone acetate or cyproterone acetate plus 30 or 35μg of ethinylestradiol produced improvement or resolution of seborrhoea in 80% of users, acne in 59–70%, hirsutism in 36% and androgen-related alopecia in up to 86%.

These COCs are generally well tolerated, the main adverse effects being nonspecific or as expected for a COC (headache, breast tenderness and nausea). They have no clinically relevant effects on metabolic or liver functions or on body-weight. Effects on mood and libido are uncommon (<3.5% and <6% of women, respectively).

COCs containing antiandrogenic progestogens are likely to be particularly valuable in women with pre-existing androgen-related disorders who require contraception. They also increase the choice of products available for women with normal skin and hair who are concerned about the possibility of developing seborrhoea or acne with other COCs.


Androgen Receptor Acne Ethinylestradiol Cyproterone Acetate Dienogest 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review/study.


  1. 1.
    Rabe T, Grunwald K, Runnebaum B. Hyperandrogenism in women. In: Runnebaum B, Rabe T, editors. Gynecological endocrinology and reproductive medicine. Vol. 1. Berlin, Heidelberg: Springer-Verlag, 1994Google Scholar
  2. 2.
    Diamanti-Kandarakis E, Tolis G, Duleba AJ. Androgens and therapeutic aspects of antiandrogens in women. J Soc Gynecol Investig 1995; 2(4): 577–92PubMedCrossRefGoogle Scholar
  3. 3.
    Slominski A, Wortsman J. Neuroendocrinology of the skin. Endocr Rev 2000; 21: 457–87PubMedCrossRefGoogle Scholar
  4. 4.
    Horton R, Tait JF. Androstenedione production and interconversion rates measured in peripheral blood and studies on the possible site of its conversion to testosterone. J Clin Invest 1966; 45: 301–12PubMedCrossRefGoogle Scholar
  5. 5.
    Bingham KDS. The metabolism of testosterone by human male scalp skin. J Endocrinol 1973; 57: 111–21PubMedCrossRefGoogle Scholar
  6. 6.
    Wilson JD, Walker JD. The conversion of testosterone to 5α-androstan-17β-ol-3-one by skin slices in man. J Clin Invest 1969; 48: 37–9Google Scholar
  7. 7.
    Andersson S, Russell DW. Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases. Proc Natl Acad Sci U S A 1990; 87: 3640–4PubMedCrossRefGoogle Scholar
  8. 8.
    Montgomery JS, Price DK, Figg WD. The androgen receptor gene and its influence on the development and progression of prostate cancer. J Pathol 2001; 195: 138–46PubMedCrossRefGoogle Scholar
  9. 9.
    Hughes IA. Minireview: sex differentiation. Endocrinology 2001; 142: 3281–7PubMedCrossRefGoogle Scholar
  10. 10.
    Rittmaster RS. Clinical relevance of testosterone and dihydrotestosterone metabolism in women. Am J Med 1995; 98: 17–21SCrossRefGoogle Scholar
  11. 11.
    Davis S. Syndromes of hyperandrogenism in women. Aust Fam Physician 1999; 28(5): 47–51Google Scholar
  12. 12.
    Hopkinson ZEC, Sattar N, Fleming R, et al. Polycystic ovarian syndrome: the metabolic syndrome comes to gynaecology. BMJ 1998; 317: 329–32PubMedCrossRefGoogle Scholar
  13. 13.
    Balen A. Pathogenesis of polycystic ovary syndrome: the enigma unravels? Lancet 1999; 354: 966–7PubMedCrossRefGoogle Scholar
  14. 14.
    Anovulation and the polycystic ovary. In: Speroff L, Glass RH, Kase NG, editors. Clinical gynecologic endocrinology and infertility. 6th ed. Baltimore (MD): Lippincott Williams & Wilkins, 1999Google Scholar
  15. 15.
    Acromite MT, Mantzoros CS, Leach RE, et al. Androgens in preeclampsia. Am J Obstet Gynecol 1999; 180: 60–3PubMedCrossRefGoogle Scholar
  16. 16.
    Laivuori H, Kaaja R, Rutanen EM, et al. Evidence of high circulating testosterone in women with prior preeclampsia. J Clin Endocrinol Metab 1998; 83(2): 344–7PubMedCrossRefGoogle Scholar
  17. 17.
    Sidelnikova VM, Orlova VG, Raisova AT, et al. Diagnosis of the causes and prevention of intrauterine fetal death in the second trimester of pregnancy in women with hyperandrogenism [in Russian]. Akush Ginekol (Mosk) 1991 Oct; (10): 16–9Google Scholar
  18. 18.
    Neumann F. The antiandrogen cyproterone acetate: discovery, chemistry, basic pharmacology, clinical use and tool in basic research. Exp Clin Endocrinol 1994; 102(1): 1–32PubMedCrossRefGoogle Scholar
  19. 19.
    Sansone G, Reisner RM. Differential rates of conversion of testosterone to dihydrotestosterone in acne and in normal human skin: possible pathogenetic factors in acne. J Invest Dermatol 1971; 56: 366–72PubMedCrossRefGoogle Scholar
  20. 20.
    Abbou CC, Colombel M, International Anandron Study Group. Efficacy of nilutamide combined with castration on bone metastases of patients with previously untreated stage M+ prostate cancer: two prospective, randomized, placebo controlled studies. Joint Bone Spine 1998; 65: 528–9Google Scholar
  21. 21.
    Battmann T, Bonfils A, Branche C, et al. RU 58841, a new specific topical antiandrogen: a candidate of choice for the treatment of acne, androgenetic alopecia and hirsutism. J Steroid Biochem Mol Biol 1994; 48: 55–60PubMedCrossRefGoogle Scholar
  22. 22.
    Matias JR, Gaillard M. Prevention of acne, hirsutism, and baldness in experimental animal models by the topical application of RU 58841, a pure non-steroidal androgen receptor inhibitor [abstract]. J Invest Dermatol 1995; 104: 577Google Scholar
  23. 23.
    Imamura K, Bonfils A, Diani A, et al. The effect of topical RU58841 (androgen receptor blocker) combined with minoxidil on hair growth in macaque androgenetic alopecia [abstract]. J Invest Dermatol 1998; 110: 679Google Scholar
  24. 24.
    Rabe T, Kowald A, Ortmann J, et al. Inhibition of skin 5α-reductase by oral contraceptive progestins in vitro. Gynecol Endocrinol 2000; 14: 223–30PubMedCrossRefGoogle Scholar
  25. 25.
    Diamanti-Kandarakis E. Current aspects of antiandrogen therapy in women. Curr Pharm Des 1999; 5: 707–23PubMedGoogle Scholar
  26. 26.
    Hammerstein J, Moltz L, Schwartz U. Antiandrogens in the treatment of acne and hirsutism. J Steroid Biochem 1983; 19(1): 591–7PubMedCrossRefGoogle Scholar
  27. 27.
    Carmina E, Lobo RA. A comparison of the relative efficacy of antiandrogens for the treatment of acne in hyperandrogenic women. Clin Endocrinol (Oxf) 2002; 57: 231–4CrossRefGoogle Scholar
  28. 28.
    Venturoli S, Ravaioli B, Bagnoli A, et al. Contraceptive and therapeutic effectiveness of two low-dose ethinylestradiol and cyproterone acetate regimens in the treatment of hirsute patients. Eur J Contracept Reprod Health Care 1998; 3: 29–33PubMedCrossRefGoogle Scholar
  29. 29.
    Committee on Safety of Drugs. Combined oral contraceptives: a statement by the committee on safety of drugs. BMJ 1970; 1: 231–2CrossRefGoogle Scholar
  30. 30.
    Bottiger LE, Boman G, Eklund G, et al. Oral contraceptives and thromboembolic disease: effects of lowering oestrogen content. Lancet 1980; I(8178): 1097–101CrossRefGoogle Scholar
  31. 31.
    Neumann F, Duesterberg B, Laurent H. Development of progestogens. In: Runnebaum B, Rabe T, Kiesel L, editors. Female contraception. Berlin, Heidelberg: Springer-Verlag, 1988Google Scholar
  32. 32.
    Kuhl H. Chemie und Pharmakologie von Chlormadinonacetat. In: Loch EG, Schramm G, editors. Chlormadinonacetat bei Androgenisierungserscheinungen. Stuttgart, New York: Schattauer, 1995: 1–12Google Scholar
  33. 33.
    Foster RH, Wilde MI. Dienogest. Drugs 1998; 56(5): 825–33PubMedCrossRefGoogle Scholar
  34. 34.
    Oettel M, Graser T, Hoffmann H, et al. The preclinical and clinical profile of dienogest: a short overview. Med Actual/Drugs Today 1999; 35 Suppl C: 3–12Google Scholar
  35. 35.
    Oettel M, Bervoas-Martin S, Elger W, et al. A 19-norprogestin without a 17α-ethinyl group I: dienogest from a pharmacokinetic point of view. Med Actual/Drugs Today 1995; 31: 499–516Google Scholar
  36. 36.
    Juchem M, Scaffrath M, Pollow K, et al. Dienogest: Bindungsstudien an verschiedenen Rezeptor-und Serumproteinen. In: Teichmann AT, editor. Dienogest: Präklinik und Klinik eines Gestagens. 2nd ed. Berlin: Walter de Gruyter, 1995: 119–33Google Scholar
  37. 37.
    Honma S, Iwamura S, Iizuka K, et al. Identification and anti-androgenic activity of the metabolites of 17α-acetoxy-6-chloropregna-4,6,-diene-,3,20-dione (chlormadinone acetate) in the rat, rabbit, dog and man. Chem Pharm Bull (Tokyo) 1977; 25: 2019–31CrossRefGoogle Scholar
  38. 38.
    Kuhl H, Jung-Hoffmann C. Pharmakologie der Gestagene. In: Kuhl H, Jung-Hoffmann C, editors. Kontrazeption. Stuttgart: Thieme, 1999: 28–31Google Scholar
  39. 39.
    Tindall D, French J, Nayfeh FS. Estradiol-17β inhibition of androgen uptake, metabolism and binding in epididymis of adult male rats in vivo: a comparison with cyproterone acetate. Steroids 1981; 37: 257–68PubMedCrossRefGoogle Scholar
  40. 40.
    Brennan DM, Kraay RJ. Chlormadinone acetate; a new highly active gestation-supporting agent. Acta Endocrinol (Copenh) 1963; 44: 367–79Google Scholar
  41. 41.
    Oettel M, Carol W, Elger W, et al. A 19-norprogestin without a 17α-ethinyl group II: dienogest from a pharmacodynamic point of view. Med Actual/Drugs Today 1995; 31: 517–36Google Scholar
  42. 42.
    Kuhl H. Pharmacokinetics of oestrogens and progestogens. Maturitas 1990; 12: 171–97PubMedCrossRefGoogle Scholar
  43. 43.
    Neumann F. The physiological action of progesterone and the pharmacological effects of progestogens: a short review. Postgrad Med J 1978; 54 Suppl. 2: 11–24PubMedGoogle Scholar
  44. 44.
    Kincl FA, Dorfman RI. Anti-ovulatory activity of subcutaneously injected steroids in the adult oestrus rabbit. Acta Endocrinol Suppl (Copenh) 1963; 73: 3–15Google Scholar
  45. 45.
    Moore C, Luderschmidt C, Moltz L, et al. Antiandrogenic properties of the dienogest-containing oral contraceptive Valette®. Med Actual/Drugs Today 1999; 35 Suppl C: 69–78Google Scholar
  46. 46.
    Dahl E, Hars R. The ultrastructure of the accessory sex organs of the male rat. Acta Endocrinol (Copenh) 1975; 80: 199–208Google Scholar
  47. 47.
    Honma S, Ugi S, Iizuka K, et al. The effects of anti-androgenic agents on metabolism and biosynthesis of testosterone: I. Testosterone metabolic regulation in the liver and the biosynthesis in the testes of rats treated with chlormadinone acetate [in Japanese]. Folia Endocrinol Jpn 1977; 53: 703–18Google Scholar
  48. 48.
    Lax ER, Baumann F, Schriefers H. Changes in the activities of microsomal enzymes involved in hepatic steroid metabolism in the rat after administration of androgenic, estrogenic, progestational, anabolic and catatonic steroids. Biochem Pharmacol 1984; 33: 1235–41PubMedCrossRefGoogle Scholar
  49. 49.
    Schürenkämper P, Lisse K. Die Metabolisierung von 4-14-C-Pregnenolon in Gewebschnitten menschlicher Ovarien und deren Beeinflussung durch Chlormadinonacetat. Endokrinologie 1975; 66: 135–44PubMedGoogle Scholar
  50. 50.
    Neumann F, Elger W. The effect of a new antiandrogenic steroid, 6-chloro-17-hydroxyl-1α.2α-methyl-enepregna-4.6-diene-3.20-dione acetate (cyproterone acetate) on the sebaceous glands of mice. J Invest Dermatol 1966; 46: 561–72Google Scholar
  51. 51.
    Ebling FJ. Factors influencing the response of the sebaceous glands of the rat to androgen. Br J Dermatol 1970; 82: 9–14CrossRefGoogle Scholar
  52. 52.
    Stötzner W, Kurischko A, Freund R, et al. Tierexperimentell-endokrinologische Charakterisierung des Gestagenes Dienogest (STS 557) II. Antigonadotrope, gestagene, androgene und antiandrogene Wirkungen. In: Stech D, Carol W (Hrsg) III, editors. Jenaer Symposium zur hormonalen Kontrazeption 1984. Jena: Friedrich-Schiller-Universität, 1985: 165–82Google Scholar
  53. 53.
    Belara® Product Monograph 1st ed. Grünenthal GmbH, 2001 AugGoogle Scholar
  54. 54.
    Hümpel M, Wendt H, Schulze P-E, et al. Bioavailability and pharmacokinetics of cyproterone actate after oral administration of 2.0mg cyproterone acetate in combination with 50 μg ethinyloestradiol to 6 young women. Contraception 1977; 15(5): 579–88PubMedCrossRefGoogle Scholar
  55. 55.
    Hümpel M, Nieuweboer B, Wendt H, et al. Investigations of pharmacokinetics of ethinylestradiol to specific consideration of possible first-pass effect in women. Contraception 1979; 19: 421–32PubMedCrossRefGoogle Scholar
  56. 56.
    Speck U, Wendt H, Schulze P-E, et al. Bioavailability and pharmacokinetics of cyproterone acetate-14C and ethinylo-estradiol-3H after oral administration as a coated tablet (SH B 209 AB). Contraception 1976; 14: 151–63PubMedCrossRefGoogle Scholar
  57. 57.
    Hobe G, Hillesheim HG, Küntzel B, et al. Studies on non-protein bound dienogest in plasma of different species [abstract]. Naunyn Schmiedebergs Arch Pharmacol Suppl 1993; 347: R44Google Scholar
  58. 58.
    Gallegos AJ, Gonzales-Diddi M, Merino M, et al. Tissue localisation of radioactive chlormadinone acetate and progesterone in the human. Contraception 1970; 1: 151–61CrossRefGoogle Scholar
  59. 59.
    Schubert K, Hobe G, Kaufmann G, et al. Synthesis, effects, and metabolism of the progestogen and potential interceptive dienogest. Presented at the International Symposium on the Chemistry of Natural Products; 1984 Jul 9–14; Poznan, Poland. In: Zalewski RI, Skolik JJ, editors. Natural products chemistry. Amsterdam: Elsevier Science Publishers, 1985: 143–58Google Scholar
  60. 60.
    Hobe G, Hillesheim HG, Schumann W, et al. Studies on pharmacokinetics of STS 557 in animal species and man. Exp Clin Endocrinol 1983; 81: 158–67PubMedCrossRefGoogle Scholar
  61. 61.
    Forchielli E, Murthy DVK. Metabolism of chlormadinone acetate in the human and laboratory animals: report from Syntex Research Center, Syntex Corporation, Palo Alto, California, 1973 Jun 14Google Scholar
  62. 62.
    Dorfman R. Chlormadinone acetate: some pharmacological, toxicological and pharmacokinetic aspects in various species. In: Kewitz H, editor. Nebenwirkungen Contrazeptiver Steroide Symposium 1970. Berlin: Westkreuz Verlag, 1971: 139–44Google Scholar
  63. 63.
    Forchielli E. Distribution, metabolism and elimination of rs-1280 after intravenous administration to dogs. Report from Syntex International ATSA, 1970 Feb 25Google Scholar
  64. 64.
    Hanasono GK, Fischer LJ. The excretion of tritium-labelled chlormadinone acetate, mestranol, norethindrone and norethynodrel in rats and the enterohepatic circulation of metabolites. Drug Metab Dispos 1974; 2: 159–68PubMedGoogle Scholar
  65. 65.
    Carol W, Klinger G, Michels W, et al. Studies on the pharmacokinetics of contraceptive steroids under steady-state conditions [in German]. Zentralb Gynakol 1991; 113: 1298–303Google Scholar
  66. 66.
    Rudolf K, Kunkel S, Rudolf H, et al. Der Einfluss von Mestranol und Chlormadinonacetat auf TSH, T4, TBC und TF4-Index beim Turner Syndrom. Zentralb Gynakol 1986; 108: 551–9Google Scholar
  67. 67.
    Lobl TJ. Androgen transport proteins: physical properties, hormonal regulation, and possible mechanism of T, CBG and ABP action. Arch Androl 1981; 7: 133–51PubMedCrossRefGoogle Scholar
  68. 68.
    Anderson DC. Sex hormone binding globulin. Clin Endocrinol 1974; 3: 69–96CrossRefGoogle Scholar
  69. 69.
    Makhzangy MN, Wynn V, Lawrence DM. Sex hormone binding globulin capacity as an index of oestrogenicity or androgenicity in women on oral contraceptive steroids. Clin Endocrinol 1979; 10: 39–45CrossRefGoogle Scholar
  70. 70.
    Ebling FJ. Hormonal control and methods of measuring sebaceous gland activity. J Invest Dermatol 1974; 62: 161–71PubMedCrossRefGoogle Scholar
  71. 71.
    van der Vange N, Blankenstein MA, Kloosterboer HJ, et al. Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, corticosteroid binding globulin, total and free testosterone. Contraception 1990; 41(4): 345–52PubMedCrossRefGoogle Scholar
  72. 72.
    Mowszowicz I, Wright F, Vincens M, et al. Androgen metabolism in hirsute patients treated with cyproterone acetate. J Steroid Biochem 1984; 20: 757–61PubMedCrossRefGoogle Scholar
  73. 73.
    Handy RW, Hess TR, Wall ME. Comparative metabolism of chlormadinone acetate [abstract]. The Pharmacologist 1973; 15: 228Google Scholar
  74. 74.
    Wiechert R, Neumann F. Gestagene Wirksamkeit von 1-Methyl-und 1.2α-Methylen-Steroiden. Arzneimittel Forschung 1965; 15: 3–16Google Scholar
  75. 75.
    Kuhl H. Comparative pharmacology of newer progestins. Drugs 1996; 51: 188–215PubMedCrossRefGoogle Scholar
  76. 76.
    Taubert HD, Kuhl H. Kontrazeption mit Hormonen. Stuttgart: Thieme, 1995Google Scholar
  77. 77.
    Rudel HW, Lebherz T, Maqueo-Topete M, et al. Assay of the anti-oestrogenic effects of progestogens in women. J Reprod Fertil 1967; 13: 199–203PubMedCrossRefGoogle Scholar
  78. 78.
    Rudel HW. Antifertility effects of low dose progestin. Fed Proc 1970; 29(3): 1228–31PubMedGoogle Scholar
  79. 79.
    Mears E, Vessey MP, Andolsek L, et al. Preliminary evaluation of four oral contraceptives containing only progestogens. BMJ 1969; 2: 730–4PubMedCrossRefGoogle Scholar
  80. 80.
    Kühne D, Seidl ST, Göretzlehner G. Contraceptive treatment with chlormadinone and its effect on the endometrium: a histological investigation. Endokrinologie 1972; 59(3): 295–306PubMedGoogle Scholar
  81. 81.
    Kühne D, Göretzlehner G, Seidl ST. Contraception with low dose chlormadinone acetate: clinical and histological results. Acta Eur Fertil 1970; 2: 75–84PubMedGoogle Scholar
  82. 82.
    Rudel HW, Kincl FA. Biology of anti-fertility steroids. Acta Endocrinol (Copenh) 1966; 51 Suppl. 105: 1–45Google Scholar
  83. 83.
    Martinez-Manautou J, Giner-Velasquez J, Cortes-Gallegos V, et al. Daily progestogen for contraception: a clinical study. BMJ 1967; 2: 730–2PubMedCrossRefGoogle Scholar
  84. 84.
    Larsson-Cohn U. Contraceptive treatment with low doses of gestagens. Acta Endocrinol Suppl (Copenh) 1970; 144 Suppl. 144: 7–46Google Scholar
  85. 85.
    Shahani SM, Munsif MK. Clinical trial with continuous low dosage (0.5 mg) chlormadinone acetate. J Biosoc Sci 1972; 4: 1–8PubMedCrossRefGoogle Scholar
  86. 86.
    Di Carlo F, Gallo E, Conti G, et al. Changes in the binding of oestradiol to uterine oestrogen receptors induced by some progesterone and 19-nor-testosterone derivatives. J Endocrinol 1983; 98: 385–9PubMedCrossRefGoogle Scholar
  87. 87.
    Kreitmann B, Bugat R, Bayard F. Estrogen and progestin regulation of the progesterone receptor concentration in human endometrium. J Clin Endocrinol Metab 1979; 49: 926–9PubMedCrossRefGoogle Scholar
  88. 88.
    Cheng CV, Boettcher B. Effects of steroids on the in vitro forward migration of human spermatozoa. Contraception 1981; 24: 183–94PubMedCrossRefGoogle Scholar
  89. 89.
    Gregoire AT, Ustay K. Effect of chlormadinone on human cervical mucus and its glycogen content. Fertil Steril 1969; 20: 938–43PubMedGoogle Scholar
  90. 90.
    Martinez-Manautou J, Cortez V, Giner J, et al. Low doses of progestogen as an approach to fertility control. Fertil Steril 1966; 17: 49–57PubMedGoogle Scholar
  91. 91.
    Martinez-Manautou J, Giner-Velasquez J, Rudel H. Continuous progestogen contraception: a dose relationship study with chlormadinone acetate. Fertil Steril 1967; 18(1): 57–62PubMedGoogle Scholar
  92. 92.
    MacDonald RR, Lumley IB, Coulson A, et al. Chlormadinone acetate as an oral contraceptive: clincal results and the incidence of ovulation. J Obstet Gynaecol Br Commonw 1968; 75: 1123–7PubMedCrossRefGoogle Scholar
  93. 93.
    Erb H. Zur Wirkung niedrig dosierter Progestagene auf die Motilität der menschlichen Tube. Geburtsh Frauenheilk 1969; 29: 255–60PubMedGoogle Scholar
  94. 94.
    Moore C, Walter F, Klinger G, et al. The influence of dienogest on ovulation in younger women and on chosen endocrinological parameters [in German]. In: Teichmann AT, editor. Dienogest: Präklinik und Klinik eines Gestagenes. 2nd ed. Berlin: Walter de Gruyter, 1995: 161–9Google Scholar
  95. 95.
    Graham S, Fraser IS. The progestogen-only minipill. Contraception 1982; 26: 373–88PubMedCrossRefGoogle Scholar
  96. 96.
    Johansson EDB. Luteolytic effect of gestagens [letter]. Acta Obstet Gynecol Scand 1971; 50: 75Google Scholar
  97. 97.
    Larsson-Cohn U, Johansson EDB, Wide L, et al. Effects of continuous daily administration of 0.5mg of chlormadinone acetate on the plasma levels of progesterone and on the urinary excretion of luteinizing hormone and total oestrogens. Acta Endocrinol (Copenh) 1970; 63: 705–16Google Scholar
  98. 98.
    Kuhl H, Jung-Hoffmann C, Storch A, et al. New aspects on the mechanism of action of contraceptive steroids: recent pharmacokinetic studies of low dose formulations. Adv Contracept 1991; Suppl. 3: 149–63Google Scholar
  99. 99.
    Oettel M, Carol W, Gräser T, et al. Effect of ethinyl estradiol-dienogest combination on serum androgen concentrations [in German]. Zentralb Gynakol 1997; 119(12): 597–606Google Scholar
  100. 100.
    Schleussner E, Michels W, Bethge S, et al. Die Wirkung von Dienogest auf die hypothalamisch-hypophysäre Achse: Ergebnisse einer Pilotstudie. In: Teichmann AT, editor. Dienogest: Präklinik und Klinik eines Gestagenes. 2nd ed. Berlin: Walter de Gruyter, 1995: 171–9Google Scholar
  101. 101.
    Gräser T, Oettel M. Organ targeting with the oral progestin dienogest. Drugs Today 1996; 32 Suppl H: 43–55Google Scholar
  102. 102.
    Erdmann D, Schindler E-M, Schindler AE. Die ovarielle Suppression unter Diane 35/50®. Geburtshilfe Frauenheilkd 1994; 54: 627–33PubMedCrossRefGoogle Scholar
  103. 103.
    Spona J, Feichtinger W, Kindermann C, et al. Modulation of ovarian function by an oral contraceptive containing 30 μg of ethinyl estradiol in combination with 2.00mg dienogest. Contraception 1997; 56: 185–91PubMedCrossRefGoogle Scholar
  104. 104.
    Hirvonen E, Stenman U-H, Mälkönen M, et al. New natural oestradiol/cyproterone acetate oral contraceptive for premenopausal women. Maturitas 1988; 10: 201–13PubMedCrossRefGoogle Scholar
  105. 105.
    Hirvonen E, Allonen H, Anttila M, et al. Oral contraceptive containing natural estradiol for premenopausal women. Maturitas 1995; 21: 27–32PubMedCrossRefGoogle Scholar
  106. 106.
    Hoffmann H, Moore C, Kovacs L, et al. Alternatives for the replacement of ethinylestradiol by natural 17β-estradiol in dienogest-containing oral contraceptives. Drugs Today 1999; 35 Suppl C: 105–13Google Scholar
  107. 107.
    Recio R, Hernández-Morales C, Pérez-Rodríguez RM, et al. Effects of low steroid doses administered in the mid and late follicular phase on the LH surge, ovarian steroids and follicular maturation in eumenorrheic women. Adv Contracept 1997; 13: 39–46PubMedCrossRefGoogle Scholar
  108. 108.
    Schramm G, Steffens D. Contraceptive efficacy and tolerability of chlormadinone acetate 2mg/ethinylestradiol 0.03mg (Belara): results of a post-marketing surveillance study. Clin Drug Invest 2002; 22(4): 221–31CrossRefGoogle Scholar
  109. 109.
    Zahradnik HP, Goldberg J, Andreas J-O. Efficacy and safety of the new antiandrogenic oral contraceptive Belara®. Contraception 1998; 57: 103–9PubMedCrossRefGoogle Scholar
  110. 110.
    Göretzlehner G. Sicherheit, Verträglichkeit und Nutzen von Chlormadinonacetat-Östrogen-Produkten. In: Loch EG, Schramm G, editors. Chlormadinonacetat bei Androgenisie-rungserscheinungen. New York, Stuttgart: Schattauer, 1995: 111–27Google Scholar
  111. 111.
    Audebert A, Emperaire JC, Gauthier A, et al. Étude clinique multicentrique d’une association de 35 μg d’éthinylestradiol et de 2mg d’acétate de cyprotérone. Rev Fr Gynecol Obstet 1991; 86: 697–9PubMedGoogle Scholar
  112. 112.
    Fugère P, Percival-Smith RKL, Lussier-Cacan S, et al. Cyproterone acetate/ethinyl estradiol in the treatment of acne: a comparative dose-response study of the estrogen component. Contraception 1990; 42(2): 225–34PubMedCrossRefGoogle Scholar
  113. 113.
    Moore C, Feichtinger W, Klinger G, et al. Clinical findings with the dienogest-containing oral contraceptive Valette®. Drugs Today 1999; 35 Suppl C: 53–68Google Scholar
  114. 114.
    Zimmermann T, Dietrich H, Wisser K-H, et al. Efficacy and tolerability of the dienogest-containing oral contraceptive Valette®: results of a postmarketing surveillance study. Drugs Today 1999; 35 Suppl C: 79–87Google Scholar
  115. 115.
    Jeppsson S, Kullander S. Experience with chlormadinone acetate in continuous low dose as an oral contraceptive. Fertil Steril 1970; 21(4): 307–13PubMedGoogle Scholar
  116. 116.
    Runnebaum B, Rabe T. Gynäkologische Endokrinologie. Berlin: Springer-Verlag, 1994: 413Google Scholar
  117. 117.
    Llewellyn-Jones D, editor. Fundamentals of obstetrics and gynaecology. Vol 2. Gynaecology. 5th ed. London: Faber and Faber Ltd, 1990Google Scholar
  118. 118.
    Breckwoldt M, Wieacker P. Hirsutismus. In: Bettendorf G, Breckwoldt M, editors. Reproduktionsmedizin. Stuttgart: Fischer, 1989: 483–7Google Scholar
  119. 119.
    Breckwoldt M, Zahradnik HP, Wieacker P. Hirsutism. In: Orfanos CE, Happle R, editors. Hair and hair diseases. Berlin: Springer-Verlag, 1990: 777–89CrossRefGoogle Scholar
  120. 120.
    Ebling FJ. Hormonal control of sebaceous glands in experimental animals. In: Montagna W, Ellis RA, Silver AF, editors. Advances in the biology of skin. Vol 4. The sebacious gland. Oxford: Pergamon Press, 1963: 200–19Google Scholar
  121. 121.
    McKenna TJ. The use of anti-androgens in the treatment of hirsutism. Clin Endocrinol (Oxf) 1991; 35: 1–3CrossRefGoogle Scholar
  122. 122.
    Dieben T, Vromans L, Theeuwes C, et al. The effects of CRT-24, a biphasic oral contraceptive combination, compared to Diane-35 in women with acne. Contraception 1994; 50: 373–82PubMedCrossRefGoogle Scholar
  123. 123.
    Redmond GP, Olson WH, Lippman JS, et al. Norgestimate and ethinylestradiol in the treatment of acne vulgaris: a randomized, placebo-controlled trial. Obstet Gynecol 1997; 89(4): 615–22PubMedCrossRefGoogle Scholar
  124. 124.
    Gollnick H, Wünsch C. The effects of an oral contraceptive containing cyproterone-acetate on acne, seborrhea and hirsutism: results of an open-label multicenter study in 890 women [abstract]. Australas J Dermatol 1997; 38 Suppl. 2: 261Google Scholar
  125. 125.
    Erkkola R, Hirvonen E, Luikku J, et al. Ovulation inhibitors containing cyproterone acetate or desogestrel in the treatment of hyperandrogenic symptoms. Acta Obstet Gynecol Scand 1990; 69: 61–5PubMedCrossRefGoogle Scholar
  126. 126.
    Charoenvisal C, Thaipisuttikul Y, Pinjaroen S, et al. Effects on acne of two oral contraceptives containing desogestrel and cyproterone acetate. Int J Fertil Menopausal Stud 1996; 41(4): 423–9PubMedGoogle Scholar
  127. 127.
    Carlborg L. Cyproterone acetate versus levonorgestrel combined with ethinylestradiol in the treatment of acne. Acta Obstet Gynecol Scand 1986; 134: 29–32CrossRefGoogle Scholar
  128. 128.
    Worret I, Arp W, Zahradnik H-P. Acne resolution rates: results of a single-blind, randomized, controlled, parallel phase III trial with EE/CMA (Belara®) and EE/LNG (Microgynon®). Dermatology 2001; 203: 38–44PubMedCrossRefGoogle Scholar
  129. 129.
    Grundy SM. Cholesterol and coronary heart disease: a new era. JAMA 1986; 256: 2849–58PubMedCrossRefGoogle Scholar
  130. 130.
    Heikki Frick M. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317: 1237–45CrossRefGoogle Scholar
  131. 131.
    Krauss RM. Effects of progestational agents on serum lipids and lipoproteins. J Reprod Med 1982; 27: 503–10PubMedGoogle Scholar
  132. 132.
    Godsland IF, Crook D, Simpson R, et al. The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med 1990; 323: 1375–81PubMedCrossRefGoogle Scholar
  133. 133.
    Porkka KVK, Erkkola R, Taimela S, et al. Influence of oral contraceptive use on lipoprotein (a) and other coronary heart disease risk factors. Ann Med 1995; 27: 193–8PubMedCrossRefGoogle Scholar
  134. 134.
    Anderson KK, Kappas A. Hormones and liver function. In: Schiff L, Schiff ER, editors. Diseases of the liver. Philadelphia (PA): JB Lippincott Co, 1982: 167–235Google Scholar
  135. 135.
    Meade TW, Haines AP. Haemostatic, lipid, and blood-pressure profiles of women on oral contraceptives containing 50μg or 30μg oestrogen. Lancet 1977; 2(8045): 948–51PubMedCrossRefGoogle Scholar
  136. 136.
    Meade TW. Risks and mechanisms of cardiovascular events in users of oral contraceptives. Am J Obstet Gynecol 1988; 158: 1646–52PubMedGoogle Scholar
  137. 137.
    Sabra A, Bonnar J. Hemostatic system changes induced by 50μg and 30μg estrogen/progestogen oral contraceptives. J Reprod Med 1983; 28: 85–91PubMedGoogle Scholar
  138. 138.
    Beck P. Alterations of lipid metabolism by contraceptive steroids. J Steroid Biochem 1975; 6: 957–9PubMedCrossRefGoogle Scholar
  139. 139.
    Lidegaard O. Oral contraception and risk of a cerebral thromboembolic attack: results of a case-control study. BMJ 1993; 306: 956–63PubMedCrossRefGoogle Scholar
  140. 140.
    Mishell Jr DR. Oral contraception: past, present and future perspectives. Int J Fertil 1991; 36: 7–18PubMedGoogle Scholar
  141. 141.
    Miccoli R, Orlandi MC, Fruzzetti F, et al. Metabolic effects of three new low-dose pills: a six-month experience. Contraception 1989; 39(6): 643–52PubMedCrossRefGoogle Scholar
  142. 142.
    Winkler UH. Chlormadinonacetate: Stoffwechsel und Hämostase. In: Loch EG, Schramm G, editors. Chlormadinonacetat bei Androgenisierungserscheinungen. Stuttgart, New York: Schattauer, 1995: 1–12Google Scholar
  143. 143.
    Winkler UH, Daume E, Sudik R, et al. A comparative study of the hemostatic effects of two monophasic oral contraceptives containing 30μg ethinylestradiol and either 2mg chlormadinone acetate or 150μg desogestrel. Eur J Contracept Reprod Health Care 1999; 4: 145–54PubMedGoogle Scholar
  144. 144.
    Spona J, Feichtinger W, Kindermann C, et al. Double-blind, randomized, placebo controlled study on the effects of the monophasic oral contraceptive containing 30μg ethinyl estradiol and 2.00mg dienogest on the hemostatic system. Contraception 1997; 56: 67–75PubMedCrossRefGoogle Scholar
  145. 145.
    Vasilakis-Scaramozza C, Jick H. Risk of venous thromboembolism with cyproterone or levonorgestrel contraceptives. Lancet 2001; 358: 1427–9PubMedCrossRefGoogle Scholar
  146. 146.
    Gompel A, Carpentier S, Frances C, et al. Risk of venous thromboembolism and oral contraceptives [letter]. Lancet 2002; 359: 1348PubMedCrossRefGoogle Scholar
  147. 147.
    World Health Organization. Collaborative study of cardiovascular disease and steroid hormone contraception. Venous thromboembolic disease and combined oral contraceptives: results of an international multicentre case-control study. Lancet 1995; 346: 1575–82Google Scholar
  148. 148.
    Jick H, Jick SS, Gurewich V, et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346: 1589–93PubMedCrossRefGoogle Scholar
  149. 149.
    Spitzer WO, Lewis MA, Heinemann LA, et al. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. BMJ 1996; 312: 83–8PubMedCrossRefGoogle Scholar
  150. 150.
    Farmer RDT, Preston TD. The risk of venous thromboembolism associated with low-dose estrogen oral contraceptives. J Obstet Gynecol 1995; 15: 195–200CrossRefGoogle Scholar
  151. 151.
    Farmer RDT, Lawrenson RA, Thompson GR, et al. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997; 349: 83–8PubMedCrossRefGoogle Scholar
  152. 152.
    Scheen AJ, Jandrain BJ, Humblet DMP, et al. Effects of a 1-year treatment with a low-dose combined oral contraceptive containing ethinyl estradiol and cyproterone acetate on glucose and insulin metabolism. Fertil Steril 1993; 59(4): 797–802PubMedGoogle Scholar
  153. 153.
    Aznar R, Lara R, Zarco D, et al. The effect of various contraceptive hormonal therapies in women with normal and diabetic oral glucose tolerance test. Contraception 1976; 13(3): 299–311PubMedCrossRefGoogle Scholar
  154. 154.
    Jandrain BJ, Humblet DMP, Jaminet CB, et al. Effects of ethinyl estradiol combined with desogestrel and cyproterone acetate on glucose tolerance and insulin response to an oral glucose load: a one-year randomized, prospective, comparative trial. Am J Obstet Gynecol 1990; 163: 378–81PubMedGoogle Scholar
  155. 155.
    Köhler G, Lembke S, Brachmann K, et al. Routine liver function testing during treatment of endometriosis with the progestin dienogest [in German]. Zentralb Gynakol 1989; 111: 807–10Google Scholar
  156. 156.
    Baum JK, Holtz F, Bookstein JJ, et al. Possible association between benign hepatomas and oral contraceptives. Lancet 1973; 2(7835): 926–9PubMedCrossRefGoogle Scholar
  157. 157.
    Rabe T, Feldmann K, Grunwald K, et al. Liver tumours and steroid hormones in women. Gynecol Endocrinol 1995; 9 Suppl. 3: 1–81Google Scholar
  158. 158.
    Rabe T, Feldmann K, Heinemann L, et al. Cyproterone acetate. Is it hepato-or genotoxic? Drug Saf 1996; 14: 25–38Google Scholar
  159. 159.
    Harris CC. Chemical and physical carcinogenesis: advances and perspectives for the 1990s. Cancer Res 1991; 51: 5023–44Google Scholar
  160. 160.
    ECETOC. DNA and protein adducts: evaluation of their use in exposure monitoring and risk assessment. Brussels: ECETOC, ECETOC Monograph No 13, 1989Google Scholar
  161. 161.
    Purchase IFH. Current knowledge of mechanisms of carcino-genicity: genotoxicity versus non-genotoxins. Hum Exp Toxicol 1994; 13: 17–28PubMedCrossRefGoogle Scholar
  162. 162.
    Fahrig R. General strategy for the assessment of genotoxicity. Mutat Res 1991; 252: 161–3PubMedCrossRefGoogle Scholar
  163. 163.
    Matthiesen T, Wöhrmann T. Chlormadinonacetat: Aspekte zur Toxikologie. In: Loch EG, Schramm G, editors. Chlormadinonacetat bei Androgenisierungserscheinungen. New York, Stuttgart: Schattauer, 1995: 29–36Google Scholar
  164. 164.
    Heinemann LAJ, Will-Shahab L. Active surveillance study on patients treated with CPA long-term: the SEHOST project. Berlin: Research Report ZEG, 1995 Jun 20Google Scholar
  165. 165.
    Beck P, Malarkey WB. Serum prolactin concentration in women treated with chlormadinone acetate. Am J Obstet Gynecol 1976; 124(6): 578–81PubMedGoogle Scholar
  166. 166.
    Testa G, Vegetti W, Motta T, et al. Two-year treatment with oral contraceptives in hyperprolactinemic patients. Contraception 1998; 58: 69–73PubMedCrossRefGoogle Scholar
  167. 167.
    Back DJ, Houlgrave R, Tna JF, et al. Effect of progestogens, gestodene, 3-ketodesogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes. J Steroid Biochem Mol Biol 1991; 38: 219–25PubMedCrossRefGoogle Scholar
  168. 168.
    Guengerich FP. Inhibition of oral contraceptive steroid metabolizing enzymes by steroids and drugs. Am J Obstet Gynecol 1990; 163: 2159–63PubMedGoogle Scholar
  169. 169.
    Böcker R, Kleingeist B, Eichorn M, et al. In vitro interaction of contraceptive steroids with human liver cytochrome P-450 enzymes. Adv Contracept 1991; 3 Suppl. 3: 140–8Google Scholar
  170. 170.
    Böcker R, Kleingeist B. Der Einfluss von Dienogest auf das humane Cytochrom P450-Enzymsystem in vitro. In: Teichmann AT, editor. Dienogest: Präklinik und Klinik eines Gestagenes. 2nd ed. Berlin: Walter de Gruyter, 1995: 141–7Google Scholar
  171. 171.
    Balogh A, Liewald T, Liewald S, et al. The influence of a new sexual steroid-dienogest-on the metabolism of caffeine and meptazimol [in German]. Zentralb Gynakol 1990; 112(12): 735–46Google Scholar
  172. 172.
    Balogh A, Gessinger S, Svarovsky U, et al. Can oral contraceptive steroids influence the elimination of nifedipine and its primary pyridine metabolite in humans? Eur J Clin Pharmacol 1998; 54: 729–34PubMedCrossRefGoogle Scholar
  173. 173.
    Kuhnz W, Löfberg B. Urinary excretion of 6β-hydroxycortisol in women during treatment with different oral contraceptive formulations. J Steroid Biochem Mol Biol 1995; 55(1): 129–33PubMedCrossRefGoogle Scholar
  174. 174.
    Goldzieher JW, Moses LE, Averkin E, et al. Nervousness and depression attributed to oral contraceptives: a double-blind, placebo-controlled study. Am J Obstet Gynecol 1971; 111(8): 1013-20PubMedGoogle Scholar

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© Adis International Limited 2003

Authors and Affiliations

  1. 1.Hôtel DieuLyonFrance
  2. 2.Universitätsklinikum FrauenklinikHeidelbergGermany

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