Metabolic effects of contraceptive steroids

Article

Abstract

Estrogen and progestins have been used by millions of women as effective combined contraceptives. The safety of hormonal contraceptives has been documented by years of follow-up and serious adverse events that may be related to their use are rare in the young population exposed to these agents. The balance between the benefits and the risks of contraceptive steroids is generally positive in particular when comparing to the risks of pregnancy and especially in women with risk factors. The metabolic changes induced by the synthetic steroids used in contraception, such as lipoprotein changes, insulin response to glucose, and coagulation factors have been considered as potential markers of cardiovascular and venous risk. Observations of these effects have led to modifications of the composition of hormonal contraceptive in order to minimize these changes and hence potentially decrease the risks. The synthetic estrogen Ethinyl-Estradiol (EE) exerts a stronger effect that natural estradiol (E2) on hepatic metabolism including estrogen-dependent markers such as liver proteins. This stronger hepatic impact of EE has been related to its 17α-ethinyl group which prevents the inactivation of the molecule and results in a more pronounced hepatic effect of EE as compared to estradiol. Due to its strong activity, administering EE via a non-oral route does not prevent its impact on liver proteins. In order to circumvent the metabolic changes induced by EE, newer products using more natural compounds such as estradiol (E2) and estradiol valerate (E2V) have been introduced. The synthetic progestins used for contraception are structurally related either to testosterone (T) (estranes and gonanes) or to progesterone (pregnanes and 19-norpregnanes). Several new progestins have been designed to bind more specifically to the progesterone receptor and to minimize side-effects related to androgenic, estrogenic or glucocorticoid receptor interactions. Dienogest (DNG), and drospirenone (DRSP) and the 19-norpregnanes including Nestorone® (NES), nomegestrol acetate (NOMAc) and trimegestone (TMG) have been combined with estrogen either EE or E2 or estradiol valerate (E2V). Risks and benefits of the newer progestins used in contraception depend upon the type of molecular structure, the type and dose of estrogen associated in a combination and the route of administration. The lower metabolic impact of estradiol-based combinations may result in an improved safety profile, but large surveillance studies are warranted to confirm this plausible hypothesis. So far, the contraindications and warnings for use of current COCs also apply to the estradiol-based COCs.

Keywords

Contraception Estrogen Progestin Lipids Carbohydrate Coagulation factors Cardiovascular 

References

  1. 1.
    Mishell Jr DR. State of the art in hormonal contraception: an overview. Am J Obstet Gynecol. 2004;190:S1–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Vaughan B, Trussell J, Kosta K, Singha S, Jonesa R. Discontinuation and resumption of contraceptive use: results from the 2002 National Survey of Family Growth. Contraception. 2008;78:271–83.PubMedCrossRefGoogle Scholar
  3. 3.
    Shufelt CL, Bairey Merz CN. Contraceptive hormone use and cardiovascular disease. J Am Coll Cardiol. 2009;53:221–31.PubMedCrossRefGoogle Scholar
  4. 4.
    Van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ. 2009;339:b2921.PubMedCrossRefGoogle Scholar
  5. 5.
    Farley TM, Collins J, Schlesselman JJ. Combined oral contraceptives, smoking, and cardiovascular risk. Contraception. 1998;57:211–30.PubMedCrossRefGoogle Scholar
  6. 6.
    Farley TM, Meirik O, Collins J. Cardiovascular disease and combined oral contraceptives: reviewing the evidence and balancing the risks. Hum Reprod Update. 1999;5:721–35.PubMedCrossRefGoogle Scholar
  7. 7.
    Benagiano G, Bastianelli C, Farris M. Hormonal contraception: present and future. Drugs Today. 2008;44:905–23.PubMedCrossRefGoogle Scholar
  8. 8.
    Committee for medicinal products for human use (CHMP). Guideline on clinical investigation of steroid contraceptives in women. Pre-authorization evaluation of medicines for human use. London: European Medicines Agency; 2005. p. 1–6.Google Scholar
  9. 9.
    Rad M, Kluft C, Ménard J, Burggraaf J, de Kam ML, Meijer P, et al. Comparative effects of a contraceptive vaginal ring delivering a nonandrogenic progestin and continuous ethinyl estradiol and a combined oral contraceptive containing levonorgestrel on hemostasis variables. Am J Obstet Gynecol. 2006;195:72–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Middeldorp S, Meijers JC, van den Ende AE, van Enk A, Bouma BN, Tans G, et al. Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study. Thromb Haemost. 2000;84:4–8.PubMedGoogle Scholar
  11. 11.
    Kemmeren JM, Algra A, Meijers JC, Bouma BN, Grobbee DE. Effects of second and third generation oral contraceptives and their respective progestagens on the coagulation system in the absence or presence of the factor V Leiden mutation. Thromb Haemost. 2002;87:199–205.PubMedGoogle Scholar
  12. 12.
    Sitruk-Ware R. Pharmacological profile of progestins. Maturitas. 2008;61:151–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Sitruk-Ware R. New progestagens for contraceptive use. Hum Reprod Update. 2006;12:169–78.PubMedCrossRefGoogle Scholar
  14. 14.
    Nath A, Sitruk-Ware R. Different cardiovascular effects of progestins according to structure and activity. Climacteric. 2009;12:96–101.PubMedCrossRefGoogle Scholar
  15. 15.
    Manning JM, Edwards IJ, Wagner WD, Wagner JD, Adams MR, Parks JS. Effects of contraceptive estrogen and progestin on the atherogenic potential of plasma LDLs in cynomolgus monkeys. Arterioscler Thromb Vasc Biol. 1997;17:1216–23.PubMedGoogle Scholar
  16. 16.
    Adams MR, Anthony MS, Manning JM, Golden DL, Parks JS. Low-dose contraceptive estrogen-progestin and coronary artery atherosclerosis of monkeys. Obstet Gynecol. 2000;96:250–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Ma PT, Yamamoto T, Goldstein JL, Brown MS. Increased mRNA for low density lipoprotein receptor in livers of rabbits treated with 17 alpha-ethinyl estradiol. Proc Natl Acad Sci USA. 1986;83:792–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Ramakrishnan G, Rana A, Das C, Chandra NC. Study of low-density lipoprotein receptor regulation by oral (steroid) contraceptives: desogestrel, levonorgestrel and ethinyl estradiol in JEG-3 cell line and placental tissue. Contraception. 2007;76:297–305.PubMedCrossRefGoogle Scholar
  19. 19.
    Kloosterboer HJ, Vonk-Noordegraaf CA, Turpijn EW. Selectivity of progesterone and androgen receptor binding of progestagens used in oral contraceptives. Contraception. 1988;38:325–32.PubMedCrossRefGoogle Scholar
  20. 20.
    Wiegratz I, Lee JH, Kutschera E, Bauer HH, von Hayn C, Moore C, et al. Effect of dienogest-containing oral contraceptives on lipid metabolism. Contraception. 2002;65:223–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Sasagawa S, Shimizu Y, Kami H, Takeuchi T, Mita S, Imada K, et al. Dienogest is a selective progesterone receptor agonist in transactivation analysis with potent oral endometrial activity due to its efficient pharmacokinetic profile. Steroids. 2008;73:222–31.PubMedCrossRefGoogle Scholar
  22. 22.
    Wiegratz I, Jung-Hoffmann C, Gross W, Kuhl H. Effect of two oral contraceptives containing ethinyl estradiol and gestodene or norgestimate on different lipid and lipoprotein parameters. Contraception. 1998;58:83–91.PubMedCrossRefGoogle Scholar
  23. 23.
    Tuppurainen M, Klimscheffskij R, Venhola M, Dieben TO. The combined contraceptive vaginal ring (NuvaRing) and lipid metabolism: a comparative study. Contraception. 2004;69:389–94.PubMedCrossRefGoogle Scholar
  24. 24.
    Kemmeren JM, Algra A, Grobbee DE. Effect of second and third generation oral contraceptives on lipid metabolism in the absence or presence of the factor V Leiden mutation. J Intern Med. 2001;250:441–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Skouby SO, Endrikat J, Düsterberg B, Schmidt W, Gerlinger C, Wessel J, et al. 1-year randomized study to evaluate the effects of a dose reduction in oral contraceptives on lipids and carbohydrate metabolism: 20 microg ethinyl estradiol combined with 100 microg levonorgestrel. Contraception. 2005;71:111–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Endrikat J, Klipping C, Cronin M, Gerlinger C, Ruebig A, Schmidt W, et al. An open label, comparative study of the effects of a dose-reduced oral contraceptive containing 20 microgethinyl estradiol and 100 microglevonorgestrel on hemostatic, lipids, and carbohydrate metabolism variables. Contraception. 2002;65:215–21.PubMedCrossRefGoogle Scholar
  27. 27.
    Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ. 2009;339:b2890.PubMedCrossRefGoogle Scholar
  28. 28.
    Klipping C, Marr J. Effects of two combined oral contraceptives containing ethinyl estradiol 20 microg combined with either drospirenone or desogestrel on lipids, hemostatic parameters and carbohydrate metabolism. Contraception. 2005;71(6):409–16.PubMedCrossRefGoogle Scholar
  29. 29.
    Taneepanichskul S, Phupong V. Influence of a new oral contraceptive with drospirenone on lipid metabolism. Gynecol Endocrinol. 2007;23:347–50.PubMedCrossRefGoogle Scholar
  30. 30.
    Gaspard U, Endrikat J, Desager JP, Buicu C, Gerlinger C, Heithecker R. A randomized study on the influence of oral contraceptives containing ethinylestradiol combined with drospirenone or desogestrel on lipid and lipoprotein metabolism over a period of 13 cycles. Contraception. 2004;69:271–8.PubMedCrossRefGoogle Scholar
  31. 31.
    von Schoultz B. Clinical efficacy and safety of combined estradiol valerate and dienogest: a new no-bleed treatment. Climacteric. 2003;6:24–32.Google Scholar
  32. 32.
    Endrikat J, Lange E, Kunz M, Schmidt W, Graeser T. A one-year randomized double-blind, multicentre study to evaluate the effects of an oestrogen-reduced, continuous combined hormone replacement therapy preparation containing 1 mg oestradiol valerate and 2 mg dienogest on metabolism in postmenopausal women. Eur J Contracept Reprod Health Care. 2007;12:229–39.PubMedCrossRefGoogle Scholar
  33. 33.
    Jensen J. Evaluation of a new estradiol oral contraceptive: estradiol valerate and dienogest. Expert Opin Pharmacother. 2010;11:1147–57.PubMedCrossRefGoogle Scholar
  34. 34.
    Parke S, Nahum GG, Mellinger U, Junge W. Metabolic effects of a new four-phasic oral contraceptive containing estradiol valerate and dienogest. Obstet Gynecol. 2008;111:15S.CrossRefGoogle Scholar
  35. 35.
    Parke S, Junge W, Mellinger U, Duijkers I, Klipping C. Oral Comparative effects of a four-phasic regimen of estradiol valerate/dienogest versus ethinylestradiol/levonorgestrel on haemostatic parameters. Hum Reprod. 2008;23:i77.CrossRefGoogle Scholar
  36. 36.
    Basdevant A, Pelissier C, Conard J, Degrelle H, Guyene TT, Thomas JL. Effects of nomegestrol acetate (5 mg/d) on hormonal, metabolic and hemostatic parameters in premenopausal women. Contraception. 1991;44:599–605.PubMedCrossRefGoogle Scholar
  37. 37.
    Ågren U, Anttila, M, Mäenpää-Liukko K, Rantala, ML, Rautiainen, H, Sommer, W et al. Effects of an oral contraceptive containing nomegestrol acetate and 17beta-estradiol on carbohydrate metabolism. In: European Society of Contraception and Reproductive Health. The Hague, The Netherlands; 2010 [abstract.]Google Scholar
  38. 38.
    Sitruk-Ware RL, Menard J, Rad M, Burggraaf J, de Kam ML, Tokay BA, et al. Comparison of the impact of vaginal and oral administration of combined hormonal contraceptives on hepatic proteins sensitive to estrogen. Contraception. 2007;75:430–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Creasy GW, Isher AC, Hall N, Shangold GA. Transdermal contraceptive patch delivering norelgestromin and ethinyl estradiol. Effects on the lipid profile. J Reprod Med. 2003;48:179–86.PubMedGoogle Scholar
  40. 40.
    Dorflinger LJ. Metabolic effects of implantable steroid contraceptives for women. Contraception. 2002;65:47–62.PubMedCrossRefGoogle Scholar
  41. 41.
    Odlind V, Milsom I, Persson I, Victor A. Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills? Acta Obstet Gynecol Scand. 2002;81:482–90.PubMedGoogle Scholar
  42. 42.
    Kuhl H. Comparative pharmacology of newer progestogens. Drugs. 1996;51:188–215.PubMedCrossRefGoogle Scholar
  43. 43.
    Newburger J, Castracane VD, Moore Jr PH, Williams MC, Goldzieher JW. The pharmacokinetics and metabolism of ethinyl estradiol and its three sulfates in the baboon. Am J Obstet Gynecol. 1983;146:80–7.PubMedGoogle Scholar
  44. 44.
    Steingold KA, Cefalu W, Pardridge W, Judd HL, Chaudhuri G. Enhanced hepatic extraction of estrogens used for replacement therapy. J Clin Endocrinol Metab. 1986;62:761–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Goebelsmann U, Mashchak CA, Mishell Jr DR. Comparison of hepatic impact of oral and vaginal administration of ethinyl estradiol. Am J Obstet Gynecol. 1985;151:868–77.PubMedGoogle Scholar
  46. 46.
    Kuhl H. Effects of progestogens on haemostasis. Maturitas. 1996;24:1–19.PubMedCrossRefGoogle Scholar
  47. 47.
    Mashchak CA, Lobo RA, Dozono-Takano R, Eggena P, Nakamura RM, Brenner PF, et al. Comparison of pharmacodynamic properties of various estrogen formulations. Am J Obstet Gynecol. 1982;144:511–8.PubMedGoogle Scholar
  48. 48.
    Kuhl H. Mechanisms of sex steroids. Future developments. Maturitas. 2004;47:285–91.PubMedCrossRefGoogle Scholar
  49. 49.
    Dinger JC, Heinemann LA, Kühl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation. Contraception. 2007;75:344–54.PubMedCrossRefGoogle Scholar
  50. 50.
    Sitruk-Ware R, Plu-Bureau G, Menard J, Conard J, Kumar S, Thalabard JC, et al. Effects of oral and trans-vaginal ethinyl estradiol on hemostatic factors and hepatic proteins in a randomized, cross-over study. J Clin Endocrinol Metab. 2007;2:2074–9.CrossRefGoogle Scholar
  51. 51.
    Oelkers W, Helmerhorst FM, Wuttke W, Heithecker R. Effect of an oral contraceptive containing drospirenone on the renin-angiotensin-aldosterone system in healthy female volunteers. Gynecol Endocrinol. 2000;14:204–13.PubMedCrossRefGoogle Scholar
  52. 52.
    Oelkers WK. Effects of estrogens and progestogens on the renin-aldosterone system and blood pressure. Steroids. 1996;61:166–71.PubMedCrossRefGoogle Scholar
  53. 53.
    Oelkers W, Schöneshöfer M, Blümel A. Effects of progesterone and four synthetic progestagens on sodium balance and the renin-aldosterone system in man. J Clin Endocrinol Metab. 1974;39:882–90.PubMedCrossRefGoogle Scholar
  54. 54.
    Wiegratz I, Lee JH, Kutschera E, Winkler UH, Kuhl H. Effect of four oral contraceptives on hemostatic parameters. Contraception. 2004;70:97–106.PubMedCrossRefGoogle Scholar
  55. 55.
    Wiegratz I, Stahlberg S, Manthey T, Sänger N, Mittmann K, Lange E, et al. Effects of conventional or extended-cycle regimen of an oral contraceptive containing 30 mcg ethinylestradiol and 2 mg dienogest on various hemostasis parameters. Contraception. 2008;78:384–91.PubMedCrossRefGoogle Scholar
  56. 56.
    Kluft C, Lansink M. Effect of oral contraceptives on haemostasis variables. Thromb Haemost. 1997;78:315–26.PubMedGoogle Scholar
  57. 57.
    van Vliet HA, Bertina RM, Dahm AE, Rosendaal FR, Rosing J, Sandset PM, et al. Different effects of oral contraceptives containing different progestogens on protein S and tissue factor pathway inhibitor. J Thromb Haemost. 2008;6:346–51.PubMedGoogle Scholar
  58. 58.
    Tans G, Curvers J, Middeldorp S, Thomassen MC, Meijers JC, Prins MH, et al. A randomized cross-over study on the effects of levonorgestrel- and desogestrel-containing oral contraceptives on the anticoagulant pathways. Thromb Haemost. 2000;84:15–21.PubMedGoogle Scholar
  59. 59.
    Rosing J, Middeldorp S, Curvers J, Christella M, Thomassen LG, Nicolaes GA, et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet. 1999;354:2036–40.PubMedCrossRefGoogle Scholar
  60. 60.
    Alhenc-Gelas M, Plu-Bureau G, Guillonneau S, Kirzin JM, Aiach M, Ochat N, et al. Impact of progestagens on activated protein C (APC) resistance among users of oral contraceptives. J Thromb Haemost. 2004;2:1594–600.PubMedCrossRefGoogle Scholar
  61. 61.
    Kluft C, Meijer P, La Guardia KD, Fisher AC. Comparison of a transdermal contraceptive patch vs. oral contraceptives on hemostasis variables. Contraception. 2008;77:77–83.PubMedCrossRefGoogle Scholar
  62. 62.
    White T, Ozel B, Jain JK, Stanczyk FZ. Effects of transdermal and oral contraceptives on estrogen-sensitive hepatic proteins. Contraception. 2006;74:293–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Jick SS, Hagberg KW, Hernandez RK, Kaye JA. Postmarketing study of ORTHO EVRA and levonorgestrel oral contraceptives containing hormonal contraceptives with 30 mcg of ethinyl estradiol in relation to nonfatal venous thromboembolism. Contraception. 2010;81:16–21.PubMedCrossRefGoogle Scholar
  64. 64.
    Jick S, Kaye JA, Li L, Jick H. Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception. 2007;76:4–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception. 2006;73:223–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Magnusdóttir EM, Bjarnadóttir RI, Onundarson PT, Gudmundsdóttir BR, Geirsson RT, Magnusdóttir SD, et al. The contraceptive vaginal ring (NuvaRing) and hemostasis: a comparative study. Contraception. 2004;69:461–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Cedars MI, Judd HL. Non oral routes of estrogen administration. Obstet Gynecol Clin North Am. 1987;14:269–98.PubMedGoogle Scholar
  68. 68.
    Edelman AB, Carlson NE, Cherala G, Munar MY, Stouffer RL, Cameron JL, et al. Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic-pituitary-ovarian activity. Contraception. 2009;80:119–27.PubMedCrossRefGoogle Scholar
  69. 69.
    Kluft C, Endrikat J, Mulder SM, Gerlinger C, Heithecker R. A prospective study on the effects on hemostasis of two oral contraceptives containing drospirenone in combination with either 30 or 20 microgethinyl estradiol and a reference containing desogestrel and 30 microgethinyl estradiol. Contraception. 2006;73:336–43.PubMedCrossRefGoogle Scholar
  70. 70.
    Winkler UH, Schindler AE, Endrikat J, Düsterberg B. A comparative study of the effects of the hemostatic system of two monophasic gestodene oral contraceptives containing 20 micrograms and 30 micrograms ethinylestradiol. Contraception. 1996;53:75–84.PubMedCrossRefGoogle Scholar
  71. 71.
    Heinemann LA, Assmann A, DoMinh T, Garbe E. Oral progestogen-only contraceptives and cardiovascular risk: results from the transnational study on oral contraceptives and the health of young women. Eur J Contracept Reprod Health Care. 1999;4:67–73.PubMedCrossRefGoogle Scholar
  72. 72.
    Conard J, Plu-Bureau G, Bahi N, Horellou MH, Pelissier C, Thalabard JC. Progestogen-only contraception in women at high risk of venous thromboembolism. Contraception. 2004;70:437–41.PubMedCrossRefGoogle Scholar
  73. 73.
    Olie V, Plu-Bureau G, Conard J, Horellou MH, Canonico M, Scarabin PY. Hormone therapy and recurrence of venous thromboembolism among postmenopausal women. Menopause. 2010. doi:10.1097/gme.0b013e3181f9f7c3.Google Scholar
  74. 74.
    Kühl C. Insulin secretion and insulin resistance in pregnancy and GDM. Implications for diagnosis and management. Diabetes. 1991;40 Suppl 2:18–24.PubMedGoogle Scholar
  75. 75.
    Picard F, Wanatabe M, Schoonjans K, Lydon J, O’Malley BW, Auwerx J. Progesterone receptor knockout mice have an improved glucose homeostasis secondary to beta -cell proliferation. Proc Natl Acad Sci USA. 2002;99:15644–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Godsland IF, Walton C, Felton C, Proudler A, Patel A, Wynn V. Insulin resistance, secretion, and metabolism in users of oral contraceptives. J Clin Endocrinol Metab. 1992;74:64–70.PubMedCrossRefGoogle Scholar
  77. 77.
    Lopez LM, Grimes DA, Schulz KF. Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus. Cochrane Database Syst Rev. 2009;4:CD006133.PubMedGoogle Scholar
  78. 78.
    Kojima T, Lindheim SR, Duffy DM, Vijod MA, Stanczyk FZ, Lobo RA. Insulin sensitivity is decreased in normal women by doses of ethinyl estradiol used in oral contraceptives. Am J Obstet Gynecol. 1993;169:1540–4.PubMedGoogle Scholar
  79. 79.
    Kulkarni HJ, Gaitonde BB, Bandisode MS. Oral contraceptives: effects on carbohydrate metabolism, insulin like activity and histology of the pancreas. Horm Metab Res. 1980;12:497–504.PubMedCrossRefGoogle Scholar
  80. 80.
    Beck P, Venable RL, Hoff DL. Mutual modification of glucose-stimulated serum insulin responses in female rhesus monkeys by ethinyl estradiol and nortestosterone derivatives. J Clin Endocrinol Metab. 1975;41:44–53.PubMedCrossRefGoogle Scholar
  81. 81.
    Godsland IF, Crook D, Simpson R, Proudler T, Felton C, Lees B, et al. The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med. 1990;323:1375–81.PubMedCrossRefGoogle Scholar
  82. 82.
    Crook D, Godsland IF, Wynn V. Oral contraceptives and coronary heart disease: modulation of glucose tolerance and plasma lipid risk factors by progestins. Am J Obstet Gynecol. 1988;158:1612–20.PubMedGoogle Scholar
  83. 83.
    Cagnacci A, Ferrari S, Tirelli A, Zanin R, Volpe A. Insulin sensitivity and lipid metabolism with oral contraceptives containing chlormadinone acetate or desogestrel: a randomized trial. Contraception. 2009;79:111–6.PubMedCrossRefGoogle Scholar
  84. 84.
    Oelkers W, Foidart JM, Dombrovicz N, Welter A, Heithecker R. Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin-aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism. J Clin Endocrinol Metab. 1995;80:1816–21.PubMedCrossRefGoogle Scholar
  85. 85.
    Knopp RH, Broyles FE, Cheung M, Moore K, Marcovina S, Chandler WL. Comparison of the lipoprotein, carbohydrate, and hemostatic effects of phasic oral contraceptives containing desogestrel or levonorgestrel. Contraception. 2001;63:1–11.PubMedCrossRefGoogle Scholar
  86. 86.
    Bergink EW, Kloosterboer HJ, Lund L, Nummi S. Effects of levonorgestrel and desogestrel in low-dose oral contraceptive combinations on serum lipids, apolipoproteins A-I and B and glycosylated proteins. Contraception. 1984;30:61–72.PubMedCrossRefGoogle Scholar
  87. 87.
    Song S, Chen JK, Yang PJ, He ML, Li LM, Fan BC, et al. A cross-over study of three oral contraceptives containing ethinyloestradiol and either desogestrel or levonorgestrel. Contraception. 1992;45:523–32.PubMedCrossRefGoogle Scholar
  88. 88.
    Cagnacci A, Ferrari S, Tirelli A, Zanin R, Volpe A. Route of administration of contraceptives containing desogestrel/etonorgestrel and insulin sensitivity: a prospective randomized study. Contraception. 2009;80:34–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Godsland IF, Gangar K, Walton C, Cust MP, Whitehead MI, Wynn V, et al. Insulin resistance, secretion, and elimination in postmenopausal women receiving oral or transdermal hormone replacement therapy. Metabolism. 1993;42:846–53.PubMedCrossRefGoogle Scholar
  90. 90.
    Dorangeon P, Thomas JL, Choisy H, Lumbroso M, Hazard MC. Effects of nomegestrol acetate on carbohydrate metabolism. Diabète Métab. 1993;19:441–5.PubMedGoogle Scholar
  91. 91.
    Halperin IJ, Kumar SS, Stroup DF, Laredo SE. The association between the combined oral contraceptive pill and insulin resistance, dysglycemia and dyslipidemia in women with polycystic ovary syndrome: a systematic review and meta-analysis of observational studies. Hum Reprod. 2011;26:191–201.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Center for Biomedical Research, Population CouncilRockefeller UniversityNew YorkUSA
  2. 2.Tietze, Population CouncilNew YorkUSA

Personalised recommendations